Quinoline Carboxamide and Quinoline Carbonitrile Derivatives as mGluR2-Negative Allosteric Modulators, Compositions, and Their Use

ABSTRACT

The present invention provides quinoline carboxamide and quinoline carbonitrile compounds of formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein ring A, R Q , -L-, R 1 , n, R 2 , and R 3  are as defined herein. The compounds of the invention are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating a patient (preferably a human) for diseases or disorders in which the mGluR2-NAM receptor is involved, including potentially Alzheimer&#39;s disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

FIELD OF THE INVENTION

The invention is directed to certain quinoline carboxamide and quinolinecarbonitrile derivatives, their salts, pharmaceutical compositionscomprising them and their use in therapy of the human body. Thequinoline carboxamide derivatives of the invention metabotropicglutamate receptor 2 (mGluR2) modulators, and hence are useful in thetreatment of Alzheimer's Disease and other diseases mediated by themGluR2 receptor.

BACKGROUND OF THE INVENTION

Alzheimer's Disease is a common neurodegenerative disease affecting theelderly, resulting in progressive memory impairment, loss of languageand visuospatial skills, and behavior deficits. Modulation ofmetabotropic glutamate receptor 2, which is prevalent in the cortex andhippocampus and regulates the release of the brain's major excitatoryneurotransmitter glutamate at key neural synapses has been demonstratedto have a major role in cognitive processing. Further, modulation ofmGluR2 improves cognitive performance in preclinical species (Higgins,G. A. et al. (2004) Pharmacological manipulation of mGlu2 receptorsinfluences cognitive performance in the rodent. Neuropharmacology 46,907-917).

The metabotropic glutamate receptors are known to contain one or moreallosteric sites, which may alter the affinity with which glutamate andother mGluR ligands bind to the primary binding or orthosteric sites. Asthe orthosteric binding site is highly conserved between all of theknown metabotropic glutamate receptors, functional selectivity may bestbe achieved through allosteric interaction with the receptor.

Certain substituted quinoline carboxamides and quinoline carbonitrilesare known in the art. See, for example, US Patent Application No.2008/0188521, WO2007/038865, WO 1996/13500, each disclosing compounds asleukotriene inhibitors, and Canadian Patent Application No. 2169231,disclosing compounds as leukotriene and SRS-A inhibitors. There remainsa need in the art for novel compounds that are effective asnon-competitive mGluR2 modulators, and/or mGluR2 negative allostericmodulators (NAMs).

SUMMARY OF THE INVENTION

The present invention provides certain novel substituted quinolinecarboxamide and quinoline carbonitrile derivatives, which arecollectively or individually referred to herein as “compound(s) of theinvention,” as described herein. The compounds of the invention areuseful as non-competitive mGluR2 antagonists, or mGluR2 negativeallosteric modulators (NAMs), and in methods of treating a patient(preferably a human) for diseases or disorders in which the mGluR2-NAMreceptor is involved, such as Alzheimer's disease, cognitive impairment,schizophrenia and other mood disorders, pain disorders and sleepdisorders, by administering to the patient a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt thereof. The invention is also directed to pharmaceuticalcompositions which include an effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, and the use of the compounds andpharmaceutical compositions of the invention in the treatment of suchdiseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the compounds of the invention have the structuralFormula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein:

ring A is a moiety selected from the group consisting of phenyl,—(C₅-C₆) cycloalkyl, —(C₅-C₆) cycloalkyenl, -pyridinyl, pyrimidinyl,-pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and -oxazolyl;

R^(Q) is selected from the group consisting of —CN and —C(O)NH₂;

-L- is a bond or a divalent moiety selected from the group consistingof:

—(C(R^(1L))₂)_(p)—,

—C(O)—, —S(O)—, and —S(O)₂—;

p is 1, 2, or 3;

each R^(1L) is independently selected from the group consisting of H,—CH₃, —CF₃, —OH, —C(O)—, halogen, -cyclopropyl, —O—CH₃, and —O—CF₃;

R¹ is selected from the group consisting of:

(1) heterocycloalkyl and heterocycloalkenyl,

wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclicor multicyclic ring systems comprising from 3 to 10 ring atoms in which1, 2, or 3 of the atoms of each said ring system is a ring heteroatomindependently selected from the group consisting of N, S, S(O), S(O)₂,and O,

and wherein each said heterocycloalkyl group and each saidheterocycloalkenyl group is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl,-alkyl-monocyclic heteroaryl, —(C₃-C₈) spirocycloalkyl, —(C₃-C₈)spiroheterocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R′)C(O)—(C₁-C₆) alkyl, —N(R^(1A))₂,—C(O)N(R^(1A))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl, wherein each R^(1A) group is independently selected from thegroup consisting of H and —(C₁-C₆ alkyl);

(2) heteroaryl,

wherein said heteroaryl is a monocyclic or multicyclic ring systemcomprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms ofsaid ring system is a ring nitrogen atom,

and wherein said heteroaryl is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl,-alkyl-monocyclic heteroaryl, —(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH,—C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl, —N(R^(1B))C(O)—(C₁-C₆) alkyl,—N(R^(1B))₂, —C(O)N(R^(1B))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆)alkyl-phenyl, —S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and—S(O)₂—(C₁-C₆) alkyl,

wherein each R^(1B) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl),

with the proviso that R¹ is not unsubstituted or substituted triazolyl,and with the further proviso that when R¹ is substituted oxadiazolyl,substituted thiazolyl, or substituted thiadiazolyl, then -L- is selectedfrom the group consisting of —(C(R^(1L))₂)_(p)—, and

(3) phenyl,

wherein said phenyl is unsubstituted or substituted with from 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, —(C₁-C₆) alkynyl, —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl,—(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R^(1C))C(O)—(C₁-C₆) alkyl, —N(R^(1C))₂,—C(O)N(R^(1C))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl,

wherein each R^(1C) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl);

(4) H and —(C₁-C₆) alkyl;

(5) —CH₂N(R^(1D))R^(1E), wherein:

-   -   R^(1D) is selected from the group consisting of H, —(C₁-C₆)        alkyl, and —C(O)OR^(1H); and    -   R^(1E) is selected from the group consisting of —O—(C₁-C₆)        alkyl, heteroalkyl,-alkyl-C(O)N(R^(1H)), and —C(O)OR^(1H),    -   wherein each R^(1H) is independently selected from the group        consisting of H and —(C₁-C₆) alkyl; and

(6) —CH₂N(R^(1F))OR^(1G), wherein:

-   -   R^(1F) is selected from the group consisting of H, —(C₁-C₆)        alkyl, and —C(O)OR^(1H), wherein each R^(1H) is independently        selected from the group consisting of H and —(C₁-C₆) alkyl; and    -   R^(1G) is selected from the group consisting of H and —(C₁-C₆)        alkyl;

n is 0, 1, 2, or 3;

each R² (when present) is independently selected from the groupconsisting of halogen, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—(C₁-C₆) haloalkyl, —O—(C₁-C₆) haloalkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —NH₂, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkyl)₂,—C(O)O(C₁-C₆) alkyl, and phenyl; and

R³ is selected from the group consisting of hydrogen and fluorine.

In one embodiment, the compounds of the invention have the structuralFormula (I.1):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein:

ring A is a moiety selected from the group consisting of phenyl,—(C₅-C₆) cycloalkyl, —(C₅-C₆) cycloalkyenl, -pyridinyl, pyrimidinyl,-pyrazolyl, and -thienyl;

R^(Q) is selected from the group consisting of —CN and —C(O)NH₂;

-L- is a bond or a divalent moiety selected from the group consistingof:

—(C(R^(1L))₂)_(p)—,

—S(O)—, and —S(O)₂—;

p is 1, 2, or 3;

each R^(1L) is independently selected from the group consisting of H,—CH₃, —CF₃, —OH, —C(O)—, halogen, -cyclopropyl, —O—CH₃, and —O—CF₃;

R¹ is selected from the group consisting of:

-   -   (1) heterocycloalkyl, heterocycloalkenyl,

wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclicor multicyclic ring systems comprising from 3 to 10 ring atoms in which1, 2, or 3 of the atoms of each said ring system is a ring heteroatomindependently selected from the group consisting of N, S, S(O), S(O)₂,and O,

and wherein each said heterocycloalkyl group and each saidheterocycloalkenyl group is unsubstituted or substituted with 1 to 4groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, wherein said alkyl is unsubstituted orsubstituted with hydroxyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl,hydroxy-substituted —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl, —(C₃-C₈)cycloalkyl, -alkyl-cycloalkyl, —CH(OH)cycloalkyl, phenyl, -alkyl-phenyl,monocyclic heteroaryl, -alkyl-monocyclic heteroaryl, —(C₃-C₈)spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆)alkyl, —N(R^(1A))C(O)—(C₁-C₆) alkyl, —N(R^(1A))₂, —C(O)N(R^(1A))₂,—S(O)₂H, S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl,

wherein each R^(1A) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl);

(2) heteroaryl,

wherein said heteroaryl is a monocyclic or multicyclic ring systemcomprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms ofsaid ring system is a ring nitrogen atom,

and wherein said heteroaryl is unsubstituted or substituted with 1 to 4groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, wherein said alkyl is unsubstituted orsubstituted with hydroxyl, —(C₁-C₆) alkynyl, —(C₁-C₆) haloalkyl,hydroxy-substituted —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl, —(C₃-C₈)cycloalkyl, -alkyl-cycloalkyl, —CH(OH)cycloalkyl, phenyl, -alkyl-phenyl,monocyclic heteroaryl, -alkyl-monocyclic heteroaryl, —(C₃-C₈)spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆)alkyl, —N(R^(1B))C(O)—(C₁-C₆) alkyl, —N(R^(1B))₂, —C(O)N(R^(1B))₂,—S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl, —S(O)₂-phenyl,—S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆) alkyl,

wherein each R^(1B) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl),

with the proviso that R¹ is not unsubstituted or substituted triazolyl,and with the further proviso that when R¹ is substituted oxadiazolyl,substituted thiazolyl, or substituted thiadiazolyl, then -L- is selectedfrom the group consisting of —(C(R^(1L))₂)_(p)—, and

(4) phenyl,

wherein said phenyl is unsubstituted or substituted with from 1 to 4groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, —(C₁-C₆) alkynyl, —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl,—(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R^(1C))C(O)—(C₁-C₆) alkyl, —N(R^(1C))₂,—C(O)N(R^(1C))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl,

wherein each R^(1C) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl);

(4) H, —(C₁-C₆) alkyl; and

(5) —CH₂N(R^(1D))R^(1E), wherein:

-   -   R^(1D) is selected from the group consisting of H, —(C₁-C₆)        alkyl, and —C(O)OR^(1H); and    -   R^(1E) is selected from the group consisting of —O—(C₁-C₆)        alkyl, heteroalkyl,-alkyl-C(O)N(R^(1H)), and —C(O)OR^(1H),    -   wherein each R^(1H) is independently selected from the group        consisting of H and —(C₁-C₆) alkyl;

n is 0, 1, 2, or 3;

each R² (when present) is independently selected from the groupconsisting of halogen, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—(C₁-C₆) haloalkyl, —O—(C₁-C₆) haloalkyl, —C(O)O(C₁-C₆) alkyl, andphenyl; and

R³ is selected from the group consisting of hydrogen and fluorine.

In one embodiment, in Formula (I), n is 0.

In one embodiment, in Formula (I), n is 1.

In one embodiment, in Formula (I), n is 2.

In one embodiment, in Formula (I), n is 3.

In one embodiment, in Formula (I), n is 0, 1, 2, or 3; and each R² isindependently selected from the group consisting of F, Cl, Br, methyl,ethyl, propyl, i-propyl, n-propyl, i-butyl, n-butyl, tert-butyl, —OCH₃,—OCH₂CH₃, —CFH₂, —CF₂H, —CF₃, —CH₂CFH₂, —CH₂CF₂H, —CH₂CF₃, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, and phenyl.

In one embodiment, the compounds of the invention have the structuralFormula (II):

or a pharmaceutically acceptable salt thereof, wherein R¹, R^(Q), -L-,n, R², and R³ are as defined in Formula (I).

An alternative embodiment of Formula (II) comprises a compound of theFormula (II.1):

or a pharmaceutically acceptable salt thereof, wherein R¹, R^(Q), -L-,n, R², and R³ are as defined in Formula (I).

Another alternative embodiment of Formula (II) comprises a compound ofthe Formula (II.2):

or a pharmaceutically acceptable salt thereof, wherein R¹, R^(Q), -L-,n, R², and R³ are as defined in Formula (I).

In one embodiment, in each of Formulas (II), (II.1), and (II.2), n is 0.

In one embodiment, in each of Formulas (II), (II.1), and (II.2) n is 1,and each R² is as defined in Formula (I).

In one embodiment, in each of Formulas (II), (Ill), and (III), n is 2,and each R² independently is as defined in Formula (I).

In one embodiment, in each of Formulas (II), (II.1), and (II.2), n is 3,and each R² is independently as defined in Formula (I).

In one embodiment, in each of Formulas (II), (II.1), and (II.2), n is 0,1, 2, or 3; and each R² is independently selected from the groupconsisting of halogen, CN, OH, —(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —O—(C₁-C₆) haloalkyl, —NH₂, —NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, and phenyl.

In one embodiment, the compounds of the invention have the structuralFormula (III):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2,the dotted line represents an optional double bond, and R¹, R^(Q), -L-,n, R², and R³ are as defined in Formula (I).

An alternative embodiment of Formula (III) comprises a compound of theFormula (III.1):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2,the dotted line represents an optional double bond, and R¹, R^(Q), -L-,n, R², and R³ are as defined in Formula (I).

Another alternative embodiment of Formula (III) comprises a compound ofthe Formula (III.2):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2,the dotted line represents an optional double bond, and R¹, R^(Q), -L-,n, R², and R³ are as defined in Formula (I).

In one embodiment, in each of Formulas (III), (III.1) and (III.2), themoiety

is selected from the group consisting of:

wherein n and each R² is defined as in Formula (I).

In one embodiment, in each of Formulas (III), (III.1) and (III.2), eachR² is independently selected from the group consisting of halogen, CN,OH, —(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl, —O—(C₁-C₆)haloalkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, and phenyl.

In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is0 and n is 0.

In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is0, n is 1, and R² is selected from the group consisting of halogen, CN,OH, —(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl, —O—(C₁-C₆)haloalkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, and phenyl.

In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is0, n is 2, and R² is independently selected from the group consisting ofhalogen, CN, OH, —(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl,—O—(C₁-C₆) haloalkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, andphenyl.

In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is0, n is 3, and R² is independently selected from the group consisting ofhalogen, CN, OH, —(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl,—O—(C₁-C₆) haloalkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, andphenyl.

In one embodiment, the compounds of the invention have the structuralFormula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a moiety selected from the group consisting of: -pyridinyl,pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and-oxazolyl; and R¹, R^(Q), -L-, n, R² and R³ are as defined in Formula(I).

An alternative embodiment of Formula (IV) comprises a compound of theFormula (IV.1):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a moiety selected from the group consisting of: -pyridinyl,pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and-oxazolyl; and R¹, R^(Q), -L-, n, R² and R³ are as defined in Formula(I).

Another alternative embodiment of Formula (IV) comprises a compound ofthe Formula (IV.2):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a moiety selected from the group consisting of: -pyridinyl,pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and-oxazolyl; and R¹, R^(Q), -L-, n, R² and R³ are as defined in Formula(I).

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring Ais pyrazolyl, which is unsubstituted or substituted with 1 to 2 R²groups.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring Ais thienyl, which is unsubstituted or substituted with 1 to 3 R² groups.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring Ais pyridinyl, which is unsubstituted or substituted with 1 to 3 R²groups.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring Ais pyrimidinyl, which is unsubstituted or substituted with 1 to 3 R²groups.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring Ais -thiazolyl, which is unsubstituted or substituted with 1 to 2 R²groups.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring Ais -thiadiazolyl, which is unsubstituted or substituted with 1 R² group.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring Ais -oxazolyl, which is unsubstituted or substituted with 1 to 2 R²groups.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 0.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 0,1, 2, or 3; and each R² is independently selected from the groupconsisting of halogen, CN, —OH, —(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —O—(C₁-C₆) haloalkyl, and phenyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 0,1, 2, or 3; and each R² is independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, phenyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 1;and each R² is independently selected from the group consisting ofhalogen, CN, —OH, —(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl,—O—(C₁-C₆) haloalkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, andphenyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 1;and R² is selected from the group consisting of halogen. In one suchembodiment, R² is fluoro.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 2;and each R² is independently selected from the group consisting ofhalogen, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, and phenyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is pyrazolyl and the moiety

is selected from the group consisting of

wherein each R² is independently as defined in Formula (I). In anothersuch embodiment, R² is selected from the group consisting of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, and phenyl. In another suchembodiment, n is 1 or 2 and each R² is independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, and phenyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is pyrazolyl and the moiety

wherein each R² is independently as defined in Formula (I). In anothersuch embodiment, R² is selected from the group consisting of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, phenyl. In another such embodiment,each R² is independently selected from the group consisting of—(C₁-C₆)alkyl and phenyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is pyrazolyl and the moiety

wherein R² is as defined in Formula (I). In another such embodiment, R²is selected from the group consisting of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, phenyl. In another such embodiment, R² is selectedfrom the group consisting of —(C₁-C₆)alkyl and phenyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is thienyl and the moiety

wherein R² is as defined in Formula (I). In another such embodiment, R²is selected from the group consisting of halo, —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and -cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is pyridinyl and the moiety

wherein R² and n are each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is pyrimidinyl and the moiety

wherein R² and n are each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is thiazolyl and the moiety

wherein R² is each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is thiazolyl and the moiety

wherein R² is each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is thiadiazolyl and the moiety

wherein R² is each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is thiadiazolyl and the moiety

wherein R² is each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is oxazolyl and the moiety

wherein R² is each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is oxazolyl and the moiety

wherein R² is each as defined in Formula (I). In another suchembodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), theRing A is oxazolyl

and the moiety wherein R² is each as defined in Formula (I). In anothersuch embodiment, R² is selected from the group consisting of halo,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -cyclopropyl, -cyclobutyl, and-cyclopentyl.

In another embodiment, the compounds of the invention have thestructural Formula (V), shown below.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

R^(Q) is CN.

In one embodiment, in each of Formulas (I), (I.1), (II), (Ill), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

R^(Q) is —C(O)NH₂.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

R³ is hydrogen.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (11.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

R³ is fluorine.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

-L- represents a covalent bond.

In one embodiment, in each of Formulas (I), (I.1), (II), (Ill), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

-L- is —C(O)—.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

-L- is —C(R^(1L))_(p)—, wherein p is 0, 1, or 2, and each R^(1L) is asdefined in Formula (I).

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (11.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

-L- is selected from the group consisting of:

-   -   —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CF₃)—, —CH(CH₃)—,        —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —C(CH₃)₂—, —CH(OH)—, —CH₂CH(OH)—,        —CH(OH)CH₂—, —CH(F)—, —CF₂—, —C(CH₃)(OH)—, —CH(OCH₃)—,

—C(O)—. —S(O)—, and —S(O)₂—.

In one embodiment, in each of Formulas (I), (I.1), (II), (Ill), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2):

-L- is selected from the group consisting of:

-   -   —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CF₃)—, —CH(CH₃)—, —CH(CH₃)CH₂—,        —CH₂CH(CH₃)—, —C(CH₃)₂—, —CH(OH)—, —CH₂CH(OH)—, —CH(OH)CH₂—,        —CH(F)—, —CF₂—, —C(CH₃)(OH)—, —CH(OCH₃)—,

and —C(O)—.

In one embodiment, in each of Formulas (I), (I.1), (II), (Ill), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is selected from the group consisting of heterocycloalkyl andheterocycloalkenyl,

wherein each of said heterocycloalkyl and said heterocycloalkenylcontains 1, 2, or 3 ring heteroatoms independently selected from thegroup consisting of N, S, S(O), S(O)2, and O, and wherein each saidheterocycloalkyl group and each said heterocycloalkenyl group isunsubstituted or substituted with 1 to 5 groups independently selectedfrom the group consisting of oxo, CN, —OH, halogen, —(C₁-C₆) alkyl,hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆) alkynyl, —(C₁-C₆)haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl,—(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl, —CH(OH)cycloalkyl, phenyl,-alkyl-phenyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl,—(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R′)C(O)—(C₁-C₆) alkyl, —N(R^(1A))₂,—C(O)N(R^(1A))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl,

and wherein each R^(1A) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl).

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is selected from the group consisting of heterocycloalkyl andheterocycloalkenyl, wherein each of said heterocycloalkyl and saidheterocycloalkenyl contains 1, 2, or 3 ring heteroatoms independentlyselected from the group consisting of N, S, S(O), S(O)2, and O, andwherein each said heterocycloalkyl group and each saidheterocycloalkenyl group is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, —CN,—OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl, —N(H)C(O)—(C₁-C₆) alkyl,—C(O)NH₂, —C(O)N(H)(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, phenyl, —(C₃-C₈)spirocycloalkyl, —(C₃-C₈) cycloalkyl, —(C₁-C₆) haloalkyl, and phenyl. Inalternatives of this embodiment, each said heterocycloalkyl group andeach said heterocycloalkenyl group is unsubstituted or substituted with1 to 4 groups, or, alternatively, 1 to 3 groups, or, alternatively 1 to2 groups, wherein each said group is independently selected from thegroup consisting of oxo, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—N(H)C(O)—(C₁-C₆) alkyl, —C(O)NH₂, —C(O)N(H)(C₁-C₆ alkyl), —C(O)N(C₁-C₆alkyl)₂, phenyl, —(C₃-C₈) spirocycloalkyl, —(C₃-C₈) cycloalkyl, —(C₁-C₆)haloalkyl, and phenyl.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is selected from the group consisting of heterocycloalkyl andheterocycloalkenyl,

wherein each of said heterocycloalkyl and said heterocycloalkenylcontains 1, 2, or 3 ring heteroatoms independently selected from thegroup consisting of N, S, S(O), S(O)2, and O,

and wherein each of said heterocycloalkyl and said heterocycloalkenyl isunsubstituted or substituted with 1 to 5 groups, alternatively 1 to 4groups, alternatively 1 to 3 groups, or, alternatively, 1 to 2 groups,independently selected from the group consisting of oxo, alkyl, —(C₃-C₈)spirocycloalkyl, —(C₃-C₈) cycloalkyl, and —(C₁-C₆) haloalkyl.

In each of the above embodiments, non-limiting examples of theheterocycloalkyl portion of said optionally substituted heterocycloalkylincludes piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, betalactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides(including N-oxides) thereof.

In each of the above embodiments, non-limiting examples of theheterocycloalkenyl portion of said optionally substitutedheterocycloalkenyl includes 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, and dihydrothiopyranyl.

In one embodiment, in each of in each of Formulas (I), (I.1), (II),(II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V),(V.1), and (V.2), le is heteroaryl,

wherein said heteroaryl is mono or bicyclic and comprises from 1 to 3ring nitrogen atoms, and wherein said heteroaryl is unsubstituted orsubstituted with 1 to 5 groups, alternatively 1 to 4 groups,alternatively 1 to 3 groups, or, alternatively, 1 to 2 groups,independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl,-alkyl-monocyclic heteroaryl, —(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH,—C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl, —N(R^(1B))C(O)—(C₁-C₆) alkyl,—N(R^(1B))₂, —C(O)N(R¹⁸)₂, —S(O)₂H, —S(O)-phenyl, S(O)—(C₁-C₆)alkyl-phenyl, —S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and—S(O)₂—(C₁-C₆) alkyl,

and wherein each R^(1B) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl),

with the proviso that R¹ is not unsubstituted or substituted triazolyl,and with the further proviso that when R¹ is substituted oxadiazolyl,substituted thiazolyl, or substituted thiadiazolyl, then -L- is selectedfrom the group consisting of —(C(R^(1L))₂)_(p)—, and

In one embodiment, in each of in each of Formulas (I), (I.1), (II),(II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V),(V.1), and (V.2), R¹ is heteroaryl,

wherein said heteroaryl is mono or bicyclic and comprises from 1 to 3ring nitrogen atoms, and wherein said heteroaryl is unsubstituted orsubstituted with 1 to 4 groups independently selected from the groupconsisting of oxo, CN, —OH, halogen, —(C₁-C₆) alkyl, hydroxy-substituted—(C₁-C₆) alkyl, —(C₁-C₆) alkynyl, —(C₁-C₆) haloalkyl,hydroxy-substituted —(C₁-C₆) haloalkyl, —O—(C₁-C₆) alkyl, —(C₃-C₈)cycloalkyl, -alkyl-cycloalkyl, —CH(OH)cycloalkyl, phenyl, -alkyl-phenyl,monocyclic heteroaryl, -alkyl-monocyclic heteroaryl, —(C₃-C₈)spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆)alkyl, —N(R^(1B))C(O)—(C₁-C₆) alkyl, —N(R^(1B))₂, —C(O)N(R^(1B))₂,—S(O)₂H, —S(O)-phenyl, S(O)—(C₁-C₆) alkyl-phenyl, —S(O)₂-phenyl,—S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆) alkyl,

and wherein each R^(1B) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl),

with the proviso that R¹ is not unsubstituted or substituted triazolyl,substituted oxadiazolyl, substituted thiazolyl, or substitutedthiadiazolyl.

In one embodiment, in each of in each of Formulas (I), (I.1), (II),(II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V),(V.1), and (V.2), R¹ is heteroaryl,

wherein said heteroaryl is mono or bicyclic and comprises from 1 to 3ring nitrogen atoms,

and wherein said heteroaryl is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, —CN,—OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl, —N(H)C(O)—(C₁-C₆) alkyl,—C(O)NH₂, —C(O)N(H)(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, phenyl, —(C₃-C₈)spirocycloalkyl, —(C₃-C₈) cycloalkyl, —(C₁-C₆) haloalkyl, and phenyl,with the proviso that R¹ is not unsubstituted or substituted triazolyl,substituted oxadiazolyl, substituted thiazolyl, or substitutedthiadiazolyl. In alternatives of this embodiment, each said heteroarylgroup is unsubstituted or substituted with 1 to 4 groups, or,alternatively, 1 to 3 groups, or, alternatively 1 to 2 groups, whereineach said group is independently selected from the group consisting ofoxo, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl, —N(H)C(O)—(C₁-C₆)alkyl, —C(O)NH₂, —C(O)N(H)(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, phenyl,—(C₃-C₈) spirocycloalkyl, —(C₃-C₈) cycloalkyl, —(C₁-C₆) haloalkyl, andphenyl, with the proviso that R¹ is not unsubstituted or substitutedtriazolyl, substituted oxadiazolyl, substituted thiazolyl, orsubstituted thiadiazolyl.

In one embodiment, in each of in each of Formulas (I), (I.1), (II),(II.1), (11.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V),(V.1), and (V.2), R¹ is selected from the group consisting ofheteroaryl,

wherein said heteroaryl is mono or bicyclic and comprise from 1 to 3ring nitrogen atoms,

and wherein said heteroaryl is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, halogen,—(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—N(R⁶)₂, —C(O)N(R⁶)₂, CN, —(C₁-C₆) haloalkyl, hydroxy-substituted—(C₁-C₆) haloalkyl, —S(O)₂H, —S(O)₂—(C₁-C₆) alkyl, and —(C₁-C₆) alkynyl,with the proviso that when R¹ is not unsubstituted or substitutedtriazolyl, substituted oxadiazolyl, substituted thiazolyl, orsubstituted thiadiazolyl. In alternatives of this embodiment, saidheteroaryl is unsubstituted or substituted with 1 to 4 groups,alternatively 1 to 3 groups, alternatively 1 to 2 groups, wherein eachsaid group is independently selected from the group consisting of oxo,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —O—(C₁-C₆)alkyl, —N(R⁶)₂, —C(O)N(R⁶)₂, CN, —(C₁-C₆) haloalkyl, hydroxy-substituted—(C₁-C₆) haloalkyl, —S(O)₂H, —S(O)₂—(C₁-C₆) alkyl, and —(C₁-C₆) alkynyl,with the proviso that when R¹ is not unsubstituted or substitutedtriazolyl, substituted oxadiazolyl, substituted thiazolyl, orsubstituted thiadiazolyl.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), and (IV.2), the heteroarylportion of said optionally substituted heteroaryl of R¹ is selected fromthe group consisting of pyridyl, pyrazinyl, furanyl, thienyl (whichalternatively may be referred to as thiophenyl), pyrimidinyl, pyridone(including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl (including 1,2,4-thiadiazolyl),pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl,quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl,isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl, andoxides (including N-oxides) thereof, and benzo-fused versions thereof,wherein each said oxadiazolyl, thiazolyl, and thiadiazolyl, whenpresent, is unsubstituted.

In one embodiment, in each of in each of Formulas (V), (V.1), and (V.2),the heteroaryl portion of said optionally substituted heteroaryl of R¹is selected from the group consisting of pyridyl, pyrazinyl, furanyl,thienyl (which alternatively may be referred to as thiophenyl),pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl,isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl (including1,2,4-thiadiazolyl), pyrazolyl, furazanyl, pyrrolyl, pyrazolyl,triazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, and benzothiazolyl, and oxides (including N-oxides)thereof, and benzo-fused versions thereof.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is phenyl, wherein said phenyl is unsubstituted or substituted with from1 to 5 groups independently selected from the group consisting of oxo,CN, —OH, halogen, —(C₁-C₆) alkyl, —(C₁-C₆) alkynyl, —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl,—(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R^(1C))C(O)—(C₁-C₆) alkyl, —N(R^(1C))₂,—C(O)N(R^(1C))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl,

and wherein each R^(1C) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl).

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is phenyl, wherein said phenyl is unsubstituted or substituted with from1 to 5 groups independently selected from the group consisting ofhalogen, —(C₁-C₆) alkyl, phenyl, —O—(C₁-C₆) alkyl, CN, —S(O)-phenyl,—S(O)₂-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl, and —S(O)₂—(C₁-C₆)alkyl-phenyl. In alternatives of this embodiment, said phenyl isunsubstituted or substituted with 1 to 4 groups, alternatively 1 to 3groups, alternatively 1 to 2 groups, wherein said said group isindependently selected from the group consisting of halogen, —(C₁-C₆)alkyl, phenyl, —O—(C₁-C₆) alkyl, CN, —S(O)-phenyl, —S(O)₂-phenyl,—S(O)—(C₁-C₆) alkyl-phenyl, and —S(O)₂—(C₁-C₆) alkyl-phenyl.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is phenyl, wherein said phenyl is unsubstituted or substituted with from1 to 5 groups independently selected from the group consisting ofhalogen, —O—(C₁-C₆) alkyl, CN, —S(O)-phenyl, —S(O)₂-phenyl,—S(O)—(C₁-C₆) alkyl-phenyl, and —S(O)₂—(C₁-C₆) alkyl-phenyl. Inalternatives of this embodiment, said phenyl is unsubstituted orsubstituted with 1 to 4 groups, alternatively 1 to 3 groups,alternatively 1 to 2 groups, wherein said said group is independentlyselected from the group consisting of halogen, —O—(C₁-C₆) alkyl, CN,—S(O)-phenyl, —S(O)₂-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl, and—S(O)₂—(C₁-C₆) alkyl-phenyl.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2),R¹-L- is selected from the group consisting of optionally substitutedphenyl, optionally substituted benzyl, and optionally substituted—CH₂CH₂-phenyl, wherein said optional substituents are one to threesubstituents independently selected from the group consisting ofhalogen, —O—(C₁-C₆) alkyl, CN, —S(O)-phenyl, —S(O)₂-phenyl,—S(O)—(C₁-C₆) alkyl-phenyl, and —S(O)₂—(C₁-C₆) alkyl-phenyl.

In one embodiment, in each of Formulas (I), (I.1), (II), (Ill), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is selected from the group consisting of H and —(C₁-C₆) alkyl.

In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2),(III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R¹is —CH₂N(R^(1D))R^(1E), wherein:

-   -   R^(1D) is selected from the group consisting of H, —(C₁-C₆)        alkyl, and —C(O)OR^(1H); and    -   R^(1E) is selected from the group consisting of —O—(C₁-C₆)        alkyl, heteroalkyl, —(C₁-C₆) alkyl-C(O)N(R^(1H)), and        —C(O)OR^(1H),    -   wherein each R^(1H) is independently selected from the group        consisting of H and —(C₁-C₆) alkyl.    -   In one embodiment, in each of Formulas (I), (I.1), (II), (III),        (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V),        (V.1), and (V.2), R¹ is —CH₂N(R^(1F))OR^(1G), wherein:    -   R^(IF) is selected from the group consisting of H, —(C₁-C₆)        alkyl, and —C(O)OR^(1H), wherein each R^(1H) is independently        selected from the group consisting of H and —(C₁-C₆) alkyl; and    -   R^(1G) is selected from the group consisting of H and —(C₁-C₆)        alkyl;

n is 0, 1, 2, or 3.

In one embodiment, the compounds of the invention comprise, collectivelyand individually, each of the example compounds shown in the tablesbelow, and pharmaceutically acceptable salts thereof. Suitablepharmaceutically acceptable salts of each of these compounds includethose discussed hereinbelow.

DEFINITIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. In the event where the chemical nameand structure for a compound of the invention disagree, the structurecontrols. These definitions apply regardless of whether a term is usedby itself or in combination with other terms, unless otherwiseindicated. Hence the definition of “alkyl” applies to “alkyl” as well asthe “alkyl” portion of “hydroxyalkyl”, “haloalkyl”, arylalkyl-,alkylaryl-, “alkoxy,” etc.

It shall be understood that, in the various embodiments of the inventiondescribed herein, any variable not explicitly defined in the context ofthe embodiment is as defined in Formula (I). All valences not explicitlyfilled are assumed to be filled by hydrogen.

In the various embodiments described herein, each variable is selectedindependently of the others unless otherwise indicated.

“Patient” includes both human and non-human animals. Non-human animalsinclude research animals and companion animals such as mice, rats,primates, monkeys, great apes, chimpanzees, canine (e.g., dogs), andfeline (e.g., house cats).

“Pharmaceutical composition” (or “pharmaceutically acceptablecomposition”) means a composition suitable for administration to apatient. Such compositions may contain the neat compound (or compounds)of the invention or mixtures thereof, or salts, solvates, prodrugs,isomers, or tautomers thereof, or they may contain one or morepharmaceutically acceptable carriers or diluents. The term“pharmaceutical composition” is also intended to encompass both the bulkcomposition and individual dosage units comprised of more than one(e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

The term “pharmaceutically acceptable” means the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound meansproviding a compound of the invention to the individual in need oftreatment in a form that can be introduced into that individual's bodyin a therapeutically useful form and therapeutically useful amount,including, but not limited to: oral dosage forms, such as tablets,capsules, syrups, suspensions, and the like; injectable dosage forms,such as IV, IM, or IP, and the like; transdermal dosage forms, includingcreams, jellies, powders, or patches; buccal dosage forms; inhalationpowders, sprays, suspensions, and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount” meanan amount of compound or a composition of the invention effective forinhibiting the herein-noted diseases and thus producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect.

As used herein, the term “treatment” or “treating” means anyadministration of a compound of the present invention and includes (1)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology), or (2) amelioratingthe disease in an animal that is experiencing or displaying thepathology or symptomatology of the diseased (i.e., reversing thepathology and/or symptomatology).

“Halogen” (or “halo”) means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octanyl, etc., each ofwhich may be straight or branched.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heteroalkyl” means an alkyl moiety as defined above, having one or morecarbon atoms, for example one, two or three carbon atoms, replaced withone or more heteroatoms, which may be the same or different, where thepoint of attachment to the remainder of the molecule is through a carbonatom of the heteroalkyl radical. Suitable such heteroatoms include O, S,S(O), S(O)₂, and —NH—, —N(alkyl)-. Non-limiting examples include ethers,thioethers, amines, and the like.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. More generally, thesuffix “ene” on alkyl, aryl, heterocycloalkyl, etc. indicates a divalentmoiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butyryl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl. “Monocyclic aryl” means phenyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or moresubstituents, which may be the same or different, as defined herein. Theprefix aza, oxa or thia before the heteroaryl root name means that atleast a nitrogen, oxygen or sulfur atom respectively, is present as aring atom. A nitrogen atom of a heteroaryl can be optionally oxidized tothe corresponding N-oxide. “Heteroaryl” may also include a heteroaryl asdefined above fused to an aryl as defined above. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl(which alternatively may be referred to as thiophenyl), pyrimidinyl,pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl,oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term“monocyclic heteroaryl” refers to monocyclic versions of heteroaryl asdescribed above and includes 4- to 7-membered monocyclic heteroarylgroups comprising from 1 to 4 ring heteroatoms, said ring heteroatomsbeing independently selected from the group consisting of N, O, and S,and oxides thereof. The point of attachment to the parent moiety is toany available ring carbon or ring heteroatom. Non-limiting examples ofmonocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridazinyl, pyridoneyl, thiazolyl, isothiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl),imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore substituents, which may be the same or different, as describedherein. Monocyclic cycloalkyl refers to monocyclic versions of thecycloalkyl moieties described herein. Non-limiting examples of suitablemonocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. Non-limiting examples of suitablemulticyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl andthe like. Further non-limiting examples of cycloalkyl include thefollowing:

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contain at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or moresubstituents, which may be the same or different, as described herein.The term “monocyclic cycloalkenyl” refers to monocyclic versions ofcycloalkenyl groups described herein and includes non-aromatic 3- to7-membered monocyclic cycloalkyl groups which contains one or morecarbon-carbon double bonds. Non-limiting examples include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohetpenyl,cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitablemulticyclic cycloalkenyl is norbomylenyl.

“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appearsin a definition of a variable in a general structure described herein,refers to the corresponding N-oxide, S-oxide, or S,S-dioxide.“Heterocyclyl” also includes rings wherein ═O replaces two availablehydrogens on the same carbon atom (i.e., heterocyclyl includes ringshaving a carbonyl group in the ring). Such ═O groups may be referred toherein as “oxo.” An example of such a moiety is pyrrolidinone (orpyrrolidone):

As used herein, the term “monocyclic heterocycloalkyl” refers monocyclicversions of the heterocycloalkyl moities described herein and include a4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to4 ring heteroatoms, said ring heteroatoms being independently selectedfrom the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)₂.The point of attachment to the parent moiety is to any available ringcarbon or ring heteroatom. Non-limiting examples of monocyclicheterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam,delta lactam, beta lactone, gamma lactone, delta lactone, andpyrrolidinone, and oxides thereof. Non-limiting examples of loweralkyl-substituted oxetanyl include the moiety:

“Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitableheterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”also includes rings wherein ═O replaces two available hydrogens on thesame carbon atom (i.e., heterocyclyl includes rings having a carbonylgroup in the ring). Example of such moiety is pyrrolidenone (orpyrrolone):

As used herein, the term “monocyclic heterocycloalkenyl” refers tomonocyclic versions of the heterocycloalkenyl moities described hereinand include 4- to 7-membered monocyclic heterocycloalkenyl groupscomprising from 1 to 4 ring heteroatoms, said ring heteroatoms beingindependently selected from the group consisting of N, N-oxide, O, S,S-oxide, S(O), and S(O)₂. The point of attachment to the parent moietyis to any available ring carbon or ring heteroatom. Non-limitingexamples of monocyclic heterocyloalkenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, andoxides thereof.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom.

there is no —OH attached directly to carbons marked 2 and 5.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Cyanoalkyl” means a NC-alkyl-group in which alkyl is as previouslydefined. Preferred cyanoalkyls contain lower alkyl. Non-limitingexamples of suitable cyanoalkyl groups include cyanomethyl and2-cyanoethyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Spriocycloalkyl” means a cycloalkyl group attached to a parent moietyat a single carbon atom. Non-limiting examples of spirocycloalkylwherein the parent moiety is a cycloalkyl include Spiro [2.5] octane,Spiro [2.4] heptane, etc. The alkyl moiety linking fused ring systems(such as the alkyl moiety in heteroarylfused heteroarylalkyl-) mayoptionally be substituted with spirocycloalkyl or other groups asdescribed herein. Non-limiting spirocycloalkyl groups includespirocyclopropyl, spriorcyclobutyl, spirocycloheptyl, andspirocyclohexyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

When a variable appears more than once in a group, e.g., R^(1A) inN(R^(1A))₂, or a variable appears more than once in a structurepresented herein, the variables can be the same or different.

The line ----, as a bond generally indicates a mixture of, or either of,the possible isomers, e.g., containing (R)- and (S)-stereochemistry. Forexample:

The wavy line

, as used herein, indicates a point of attachment to the rest of thecompound. Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

“Oxo” is defined as a oxygen atom that is double bonded to a ring carbonin a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or otherring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

In another embodiment, the compounds of the invention, and/orcompositions comprising them, are present in isolated and/or purifiedform. The term “purified”, “in purified form” or “in isolated andpurified form” for a compound refers to the physical state of saidcompound after being isolated from a synthetic process (e.g. from areaction mixture), or natural source or combination thereof. Thus, theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound (or atautomer or stereoisomer thereof, or pharmaceutically acceptable salt orsolvate of said compound, said stereoisomer, or said tautomer) afterbeing obtained from a purification process or processes described hereinor well known to the skilled artisan (e.g., chromatography,recrystallization and the like), in sufficient purity to be suitable forin vivo or medicinal use and/or characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It shall be understood that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

Another embodiment provides prodrugs and/or solvates of the compounds ofthe invention. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress. The term “prodrug” means a compound (e.g, a drug precursor) thatis transformed in vivo to yield a compound of the invention or apharmaceutically acceptable salt, hydrate or solvate of the compound.The transformation may occur by various mechanisms (e.g., by metabolicor chemical processes), such as, for example, through hydrolysis inblood. A discussion of the use of prodrugs is provided by T. Higuchi andW. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

For example, if a compound of the invention or a pharmaceuticallyacceptable salt thereof, contains a carboxylic acid functional group, aprodrug can comprise an ester formed by the replacement of the hydrogenatom of the acid group with a group such as, for example, (C₁-C₈)alkyl,(C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbonatoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of the invention incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₆) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of the invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

Another embodiment provides pharmaceutically acceptable salts of thecompounds of the invention. Thus, reference to a compound of theinvention herein is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s)”, as employed herein,denotes acidic salts formed with inorganic and/or organic acids, as wellas basic salts formed with inorganic and/or organic bases. In addition,when a compound of the invention contains both a basic moiety, such as,but not limited to a pyridine or imidazole, and an acidic moiety, suchas, but not limited to a carboxylic acid, zwitterions (“inner salts”)may be formed and are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the invention may be formed, for example, byreacting a compound of the invention with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like.

Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Another embodiment provides pharmaceutically acceptable esters of thecompounds of the invention. Such esters include the following groups:(1) carboxylic acid esters obtained by esterification of the hydroxygroups, in which the non-carbonyl moiety of the carboxylic acid portionof the ester grouping is selected from straight or branched chain alkyl(for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (forexample, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl(for example, phenoxymethyl), aryl (for example, phenyl optionallysubstituted with, for example, halogen, C₁₋₄alkyl, or C₁₋₄alkoxy oramino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (forexample, methanesulfonyl); (3) amino acid esters (for example, L-valylor L-isoleucyl); (4) phosphonate esters and (5) mono-, di- ortriphosphate esters. The phosphate esters may be further esterified by,for example, a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di (C₆₋₂₄)acyl glycerol.

Another embodiment provides tautomers of the compounds of the invention,and salts, solvates, esters and prodrugs thereof. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Another embodiment provides for diastereomeric mixtures and individualenantiomers of the compounds of the invention. Diastereomeric mixturescan be separated into their individual diastereomers on the basis oftheir physical chemical differences by methods well known to thoseskilled in the art, such as, for example, by chromatography and/orfractional crystallization. Enantiomers can be separated by convertingthe enantiomeric mixture into a diastereomeric mixture by reaction withan appropriate optically active compound (e.g., chiral auxiliary such asa chiral alcohol or Mosher's acid chloride), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. Also, some of thecompounds of the invention may be atropisomers (e.g., substitutedbiaryls) and are considered as part of this invention. Enantiomers canalso be separated by use of chiral HPLC column.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the compounds of the invention (including those of thesalts, solvates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated as embodiments within the scope of this invention, as arepositional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (Forexample, if a compound of the invention incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

In the compounds of the invention, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the invention. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Additional examples of isotopes that can be incorporated intocompounds of the invention include (when present) isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

In an additional embodiment, the compounds of the invention areisotopically labeled for use as research or diagnostic agents. Forexample, compounds of the invention can be labeled for use in compoundand/or substrate tissue distribution assays. Tritiated (i.e., ³H) andcarbon-14 (i.e., ¹⁴C) isotopes are preferred for their ease ofpreparation and detectability. In another embodiment, the compounds ofthe invention can be labeled with heavier isotopes such as deuterium(i.e., ²H). Deuterium enrichment of the compounds of the invention mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements), or may provide a compound useful as a standard forcharacterization of biological samples, and hence may be preferred insome circumstances. Isotopically labelled compounds of the invention cangenerally be prepared without undue experimentation by followingprocedures analogous to those disclosed in the Schemes and/or in theExamples hereinbelow, by substituting an appropriate isotopicallylabelled reagent for a non-isotopically labelled reagent.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Compositions and Administration

Another embodiment provides pharmaceutical compositions which comprise atherapeutically effective amount of a compound of the invention, or asteroisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, and a pharmaceutically acceptablecarrier.

A preferred dosage is about 0.001 to 100 mg/kg of body weight/day of thecompound of the invention. An especially preferred dosage is about 0.01to 10 mg/kg of body weight/day of a compound of the invention, or apharmaceutically acceptable salt of said compound.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional therapeutic agentselected from the lists of the additional agents described herein below,along with any pharmaceutically inactive excipients. The bulkcomposition and each individual dosage unit can contain fixed amounts ofthe aforesaid “more than one pharmaceutically active agents”. The bulkcomposition is material that has not yet been formed into individualdosage units. An illustrative dosage unit is an oral dosage unit such astablets, pills and the like. Similarly, the herein-described method oftreating a patient by administering a pharmaceutical composition of thepresent invention is also intended to encompass the administration ofthe afore-said bulk composition and individual dosage units.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories.

The powders and tablets may be comprised of from about 5 to about 95percent active ingredient. Suitable solid carriers are known in the art,e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.Examples of materials useful for forming such liquid form preparationsinclude water or water-propylene glycol solutions for parenteralinjection, or sweeteners and opacifiers for oral solutions, suspensionsand emulsions. Liquid form preparations may also include solutions orsuspensions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention can also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.001 mg to about 100 mg per kg bodyweight of a mammal, preferably from about 0.01 mg to about 10 mg per kg.The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The compositions of the invention can further comprise one or moreadditional therapeutic agents, as discussed in further detail below.Accordingly, in one embodiment, the present invention providescompositions comprising: (i) a compound of the invention, or astereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer; (ii) one or more additional therapeuticagents, that are not compounds of the invention; and (iii) apharmaceutically acceptable carrier, wherein the amounts in thecomposition are together effective to treat one of the disease orconditions discussed herein.

Uses of the Compounds of the Invention

Another embodiment provides a method of treating a patient (e.g., ahuman patient or a research animal) for diseases or disorders in whichthe mGluR2 receptor is involved. These methods comprise administering aneffective amount of a compound of the invention, or compositioncomprising a compound of the invention (or a stereoisomer thereof, or apharmaceutically acceptable salt of said compound or said stereoismer),to a patient in need thereof, to treat a disease or disorder in whichthe mGluR2 receptor is involved.

Another embodiment provides for the use of a compound of the inventionfor treating a disease or disorder in which the mGluR2 receptor isinvolved, by administering an effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, to a patientin need thereof.

In one embodiment, the compounds of the invention useful in said methodsor said uses comprise a compound according to any one of Formulas (I),(I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1),(IV.2), (V), (V.1), and/or (V.2), as described above, or according toany of the various embodiments described above. In another embodiment,the compounds of the invention useful in said methods and said usescomprise the compounds of the examples, e.g., as set forth in the Tablesbelow.

Another embodiment comprises a method of using, in each of the methodsand/or uses described herein, a compound according to Formula (I.2):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein:

R¹ is heteroaryl,

wherein said heteroaryl is a monocyclic or multicyclic ring systemcomprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms ofsaid ring system is a ring nitrogen atom,

and wherein said heteroaryl is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl,-alkyl-monocyclic heteroaryl, —(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH,—C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl, —N(R^(1B))C(O)—(C₁-C₆) alkyl,—N(R^(1B))₂, —C(O)N(R^(1B))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆)alkyl-phenyl, —S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and—S(O)₂—(C₁-C₆) alkyl,

wherein each R^(1B) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl);

and -L-, R³, R^(Q), Ring A, R², and n are each as described in Formula(I.1) above.

Another embodiment comprises a method of using, in each of the methodsand/or uses described herein, a compound according to Formula (V):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein:

ring A is a moiety selected from the group consisting of: phenyl,—(C₅-C₆) cycloalkyl, —(C₅-C₆) cycloalkyenl, -pyridinyl, pyrimidinyl,-pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and -oxazolyl;

R^(Q) is selected from the group consisting of —CN and —C(O)NH₂;

-L- is a bond or a divalent moiety selected from the group consistingof:

—(C(R^(1L))₂)_(p)—,

—C(O)—, —S(O)—, and —S(O)₂—;

p is 1, 2, or 3;

each R^(1L) is independently selected from the group consisting of H,—CH₃, —CF₃, —OH, —C(O)—, halogen, -cyclopropyl, —O—CH₃, and —O—CF₃;

R¹ is selected from the group consisting of:

(1) heterocycloalkyl, heterocycloalkenyl,

wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclicor multicyclic ring systems comprising from 3 to 10 ring atoms in which1, 2, or 3 of the atoms of each said ring system is a ring heteroatomindependently selected from the group consisting of N, S, S(O), S(O)₂,and O,

and wherein each said heterocycloalkyl group and each saidheterocycloalkenyl group is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl,-alkyl-monocyclic heteroaryl, —(C₃-C₈) spirocycloalkyl, —(C₃-C₈)spiroheterocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R^(1A))C(O)—(C₁-C₆) alkyl, —N(R^(1A))₂,—C(O)N(R^(1A))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl, wherein each R^(1A) group is independently selected from thegroup consisting of H and —(C₁-C₆ alkyl);

(2) heteroaryl,

wherein said heteroaryl is a monocyclic or multicyclic ring systemcomprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms ofsaid ring system is a ring nitrogen atom,

and wherein said heteroaryl is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl,-alkyl-monocyclic heteroaryl, —(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH,—C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl, —N(R′)C(O)—(C₁-C₆) alkyl,—N(R^(1B))₂, —C(O)N(R^(1B))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆)alkyl-phenyl, —S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and—S(O)₂—(C₁-C₆) alkyl,

wherein each R^(1B) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl);

(5) phenyl,

wherein said phenyl is unsubstituted or substituted with from 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, —(C₁-C₆) alkynyl, —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl,—(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R^(1C))C(O)—(C₁-C₆) alkyl, —N(R^(1C))₂,—C(O)N(R^(1C))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl,

wherein each R^(1C) group is independently selected from the groupconsisting of H and —(C₁-C₆ alkyl);

(4) H, —(C₁-C₆) alkyl;

(5) —CH₂N(R^(1D))R^(1F), wherein:

-   -   R^(1D) is selected from the group consisting of H, —(C₁-C₆)        alkyl, and —C(O)OR^(1H); and    -   R^(1E) is selected from the group consisting of —O—(C₁-C₆)        alkyl, heteroalkyl,-alkyl-C(O)N(R^(1H)), and —C(O)OR^(1H),        wherein each R^(1H) is independently selected from the group        consisting of H and —(C₁-C₆) alkyl; and

(6) —CH₂N(R^(1F))OR^(1G), wherein:

-   -   R^(1F) is selected from the group consisting of H, —(C₁-C₆)        alkyl, and —C(O)OR^(1H), wherein each R^(1H) is independently        selected from the group consisting of H and —(C₁-C₆) alkyl; and    -   R^(1G) is selected from the group consisting of H and —(C₁-C₆)        alkyl;

n is 0, 1, 2, or 3;

each R² (when present) is independently selected from the groupconsisting of halogen, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—(C₁-C₆) haloalkyl, —O—(C₁-C₆) haloalkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —NH₂, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkyl)₂,—C(O)O(C₁-C₆) alkyl, and phenyl; and

R³ is selected from the group consisting of hydrogen and fluorine.

An alternative embodiment of the compounds of Formula (V) useful in saidmethods or said uses comprises a compound according to Formula (V.1):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein each of R¹, -L-, Ring A, R², n,R³, and R^(Q) are as defined in Formula (V).

Another alternative embodiment of the compounds of Formula (V) useful insaid methods or said uses comprises a compound according to Formula(V.2):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein each of R¹, -L-, Ring A, R², n,R³, and R^(Q) are as defined in Formula (V).

In alternative embodiments of Formulas (V), (V.1) and (V.2), when R¹ isheterocycloalkyl, heterocycloalkenyl, heteroaryl, or phenyl, each saidR¹ group is unsubstituted or substituted with 1 to 4 groups, or,alternatively, 1 to 3 groups, or, alternatively 1 to 2 groups, whereineach said group is as defined in Formula (V).

Diseases or disorders in which the mGluR2 receptor may be involvedinclude, but are not limited to, Alzheimer's Disease, cognitiveimpairment, schizophrenia, mood disorders, including depression andanxiety, gastrointestinal disorders, pain disorders and sleep disorders.

Additional examples of pain disorders include acute pain, inflammatorypain and neuropathic pain. Neuropathic pain includes, but is not limitedto, postherpetic neuralgia, nerve injury, the “dynias”, e.g.,vulvodynia, phantom limb pain, root avulsions, painful diabeticneuropathy, painful traumatic mononeuropathy, painful polyneuropathy.Additional examples of pain disorders include central pain syndromes(potentially caused by virtually any lesion at any level of the nervoussystem); postsurgical pain syndromes (eg, postmastectomy syndrome,postthoracotomy syndrome, stump pain); bone and joint pain(osteoarthritis), repetitive motion pain, dental pain, cancer pain,myofascial pain (muscular injury, fibromyalgia); perioperative pain(general surgery, gynecological), chronic pain, dysmennorhea, as well aspain associated with angina, and inflammatory pain of varied origins(e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease,teno-synovitis and gout), headache, migraine and cluster headache,headache, primary hyperalgesia, secondary hyperalgesia, primaryallodynia, secondary allodynia, or other pain caused by centralsensitization.

Additional examples of cognitive disorders include mild cognitiveimpairment. Other conditions that may be treated by the compounds andcompositions of the invention include Parkinson's Disease, pulmonaryhypertension, chronic obstructive pulmonary disease (COPD), asthma,urinary incontinence, glaucoma, Trisomy 21 (Down Syndrome), cerebralamyloid angiopathy, degenerative dementia, Hereditary CerebralHemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D),Creutzfeld-Jakob disease, prion disorders, amyotrophic lateralsclerosis, progressive supranuclear palsy, head trauma, stroke,pancreatitis, inclusion body myositis, other peripheral amyloidoses,diabetes, autism and atherosclerosis.

In preferred embodiments, the compounds of the invention may be usefulin treating Alzheimer's Disease, cognitive disorders, schizophrenia,pain disorders and sleep disorders. For example, the compounds may beuseful for the prevention of dementia of the Alzheimer's type, as wellas for the treatment of early stage, intermediate stage or late stagedementia of the Alzheimer's type.

Potential schizophrenia conditions or disorders for which the compoundsof the invention may be useful include one or more of the followingconditions or diseases: schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketanine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illness associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome), including both the positiveand the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orage related cognitive decline.

In another embodiment, the present invention provides a method fortreating schizophrenia or psychosis comprising administering to apatient in need thereof an effective amount of a compound (orcomposition providing a compound) of the invention, or a stereoisomerthereof.

Potential sleep conditions or disorders for which the compounds of theinvention may be useful include enhancing sleep quality; improving sleepquality; augmenting sleep maintenance; increasing the value which iscalculated from the time that a subject sleeps divided by the time thata subject is attempting to sleep; decreasing sleep latency or onset (thetime it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleepapnea; wakefulness; nocturnal myoclonus; REM sleep interruptions;jet-lag; shift workers' sleep disturbances; dyssomnias; night terror;insomnias associated with depression, emotional/mood disorders, as wellas sleep walking and enuresis, and sleep disorders which accompanyaging; Alzheimer's sundowning; conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules;conditions due to drugs which cause reductions in REM sleep as a sideeffect; syndromes which are manifested by non-restorative sleep andmuscle pain or sleep apnea which is associated with respiratorydisturbances during sleep; and conditions which result from a diminishedquality of sleep.

Compounds of the invention may also be used to treat or preventdyskinesias. Furthermore, compounds of the invention may be used todecrease tolerance and/or dependence to opioid treatment of pain, andfor treatment of withdrawal syndrome of e.g., alcohol, opioids, andcocaine.

The subject or patient to whom the compounds of the present invention isadministered is generally a human being, male or female, in whom mGluR2receptor inhibition is desired, but may also encompass other mammalssuch as those listed above, including dogs, cats, mice, rats, cattle,horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates,for which treatment the above noted disorders, or the study of mGluR2,is desired.

Another embodiment provides a medicament or pharmaceutical compositionfor the inhibition of mGluR2 receptor, and/or for the treatment of anyof the diseases or disorders listed above to a patient (preferably ahuman) in need of such treatment, which comprise a compound (orcomposition comprising a compound) of the invention, or a stereoisomerthereof, or a pharmaceutically acceptable salt of said compound or saidstereoisomer, and a pharmaceutically acceptable carrier.

Another embodiment provides a method for the manufacture of a medicamentor a pharmaceutical composition for the inhibition of an mGluR2-NAMreceptor, and/or for treating one or more diseases or conditions listedabove, comprising combining a compound (or composition comprising acompound) of the invention, or a stereoisomer thereof, or apharmaceutically acceptable salt of said compound or said stereoisomer,with a pharmaceutically acceptable carrier.

Combination Therapy

The compounds and compositions of the invention may be used incombination with one or more other drugs in the treatment of diseases orconditions for which the compounds of the invention have utility, wherethe combination of the drugs is desired, e.g., where the combination issafer or more effective than either drug alone. Additionally, thecompounds of the invention may be used in combination with one or moreother drugs that treat, prevent, control, ameliorate, or reduce the riskof side effects or toxicity of the compounds of the invention. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with the compounds ofthe present invention. Accordingly, the pharmaceutical compositions ofthe present invention include those that contain one or more otheractive ingredients, in addition to the compounds of the presentinvention. The combinations may be administered as part of a unit dosageform combination product, or as a kit or treatment protocol wherein oneor more additional drugs are administered in separate dosage forms aspart of a treatment regimen. In one embodiment, the compounds of theinvention useful in said combinations comprise a compound according toany one of Formulas (I), (I.1), (I.2), (II), (II.1), (II.2), (III),(III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and/or (V.2) asdescribed herein, or according to any of the various embodimentsdescribed herein. In another embodiment, the compounds of the inventionuseful in said combinations comprise the compounds of the examples,e.g., as set forth as example compounds of the invention in the Tablesherein.

In another embodiment, a compound or composition of the invention may beemployed in combination with acetylcholinesterase inhibitors such asdonepezil and rivastigmine, NMDA antagonist such as memantine,muscarinic receptor modulators, AMPA receptor modulators, mGluR3receptor modulators, nicotinic alpha-7 and alpha4-beta 2 receptormodulators, 5-HT6 and 5-HT4 receptor modulators, modulators ofphosphodiesterases (PDEs), alpha 2c receptor anagonists, histonedeacetylases, and antioxidant therapies.

In another embodiment, a compound or composition of the invention may beemployed in combination with therapies that may alter or modify thecourse of disease progression, including beta-amyloid modulatingtherapies such as BACE1 inhibitors, gamma-secretase modulators, tauand/or phosphor-tau modulators, and biologic therapies which modulateplacques associated with neurological disorders including antibodies,RNAi, miRNA, and cell-therapies.

In another embodiment, a compound or composition of the invention may beemployed in combination with levodopa (with or without a selectiveextracerebral decarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide or pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

Additional examples of combinations of the compounds includecombinations with agents for the treatment of pain, for examplenon-steroidal anti-inflammatory agents, such as aspirin, diclofenac,duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac andtolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib,406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-1antagonists, such as AMG517, 705498, 782443, PAC20030, V114380 andA425619; bradykinin B 1 receptor antagonists, such as SSR240612 andNVPSAA164; sodium channel blockers and antagonists, such as VX409 andSPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOSinhibitors), such as SD6010 and 274150; glycine site antagonists,including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDAantagonists, such as AZD4282; potassium channel openers; AMPA/kainatereceptor antagonists; calcium channel blockers, such as ziconotide andNMED160; GABA-A receptor IO modulators (e.g., a GABA-A receptoragonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents;opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol,meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine,propoxyphene; neutrophil inhibitory factor (NIF); pramipexole,ropinirole; anticholinergics; amantadine; monoamine oxidase B15(“MAO-B”) inhibitors; 5HT receptor agonists or antagonists; mGlu5antagonists, such as AZD9272; alpha agonists, such as AGNXX/YY; neuronalnicotinic agonists, such as ABT894; NMDA receptor agonists orantagonists, such as AZD4282; NKI antagonists; selective serotoninreuptake inhibitors (“SSRI”) and/or selective serotonin andnorepinephrine reuptake inhibitors (“SSNRI”), such as duloxetine;tricyclic antidepressant drugs, norepinephrine modulators; lithium;valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan;naratriptan and sumatriptan.

In another embodiment, the compounds and compositions of the inventionmay be administered in combination with compounds useful for thetreatment of schizophrenia or enhancing sleep quality and preventing andtreating sleep disorders and sleep disturbances, including e.g.,sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents,antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexinantagonists, alpha-1 antagonists, GABA agonists, 5HT-2 antagonistsincluding 5HT-2A antagonists and 5HT-2A/2C antagonists, histamineantagonists including histamine H3 antagonists, histamine H3 inverseagonists, imidazopyridines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, other orexin antagonists, orexinagonists, prokineticin agonists and antagonists, pyrazolopyrimidines,T-type calcium channel antagonists, triazolopyridines, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.

In one embodiment, the compound of the invention is administered duringa time when the additional therapeutic agent(s) exert their prophylacticor therapeutic effect, or vice versa.

In another embodiment, the compound of the invention and the additionaltherapeutic agent(s) are administered in doses commonly employed whensuch agents are used as monotherapy for treating the disorder.

In another embodiment, the compound of the invention and the additionaltherapeutic agent(s) are administered in doses lower than the dosescommonly employed when such agents are used as monotherapy for treatingthe disorder.

In one embodiment, the compound of the invention and the additionaltherapeutic agent(s) are present in the same composition, which issuitable for oral administration.

In some embodiments, the compound of the invention and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

The doses and dosage regimen of the additional therapeutic agent(s) usedin the combination therapies of the present invention for the treatmentor prevention of a disease or disorder can be determined by theattending clinician, taking into consideration the approved doses anddosage regimen in the package insert; the age, sex and general health ofthe patient; and the type and severity of the viral infection or relateddisease or disorder.

Another embodiment provides a kit comprising a therapeutically effectiveamount of the compound (or a composition comprising a compound) of theinvention, or a stereoisomer thereof, or a pharmaceutically acceptablesalt of said compound or said stereoisomer, optionally together with atleast one additional therapeutic agent listed above, and apharmaceutically acceptable carrier, vehicle or diluent.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.

In one embodiment, the compound of the invention is administered duringa time when the additional therapeutic agent(s) exert their prophylacticor therapeutic effect, or vice versa.

In another embodiment, the compound of the invention and the additionaltherapeutic agent(s) are administered in doses commonly employed whensuch agents are used as monotherapy for treating the disorder.

In another embodiment, the compound of the invention and the additionaltherapeutic agent(s) are administered in doses lower than the dosescommonly employed when such agents are used as monotherapy for treatingthe disorder.

In one embodiment, the compound of the invention and the additionaltherapeutic agent(s) are present in the same composition, which issuitable for oral administration.

Preparative Examples

In general, the compounds in the invention may be produced by a varietyof processes known to those skilled in the art and by know, processesanalogous thereto. The invention disclosed herein is exemplified by thefollowing preparations and examples which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures will be apparent to those skilled in the art. Thepractitioner is not limited to these methods.

One skilled in the art will recognize that one route will be optimizeddepending on the choice of appendage substituents. Additionally, oneskilled in the art will recognize that in some cases the order of stepshas to be controlled to avoid functional group incompatability.

The prepared compounds may be analyzed for their composition and purityas well as characterized by standard analytical techniques such as, forexample, elemental analysis, NMR, mass spectroscopy and IR spectra.

One skilled in the art will recognize that reagents and solventsactually used may be selected from several reagents and solvents wellknown in the art to be effective equivalents. Hence, when a specificsolvent or reagent is mentioned, it is meant to be an illustrativeexample of the conditions desirable for that particular reaction schemeor for the preparation described below.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-400 (400 MHz, ¹H), Varian Gemini-300 (300 MHz), VarianMercury VX-400 (400 MHz), Bruker-Biospin AV-500 (500 MHz) or BrukerAvance DRX-500 (500 MHz), and chemical shifts are reported as ppm withnumber of protons and multiplicities indicated parenthetically. WhereLC/MS data are presented, analyses was performed using a 1200 seriesAgilent 6140 Quadrupole LCMS with a 1.8 μM Zorbax SB-C₁₈ column (10-95%of MeCN—H2O with 0.1% TFA over 2.7 min, 1 mL/min) or with an AppliedBiosystems API-150 mass spectrometer and Gemini C₁₈ column (50×4.6 mm,10-95% CH₃CN-1120 with 0.05% TFA over 5 min, 1 mL/min).

Preparative chiral HPLC separations were generally carried out usingsupercritical fluid chromatography by eluting a chiral column such asOJ-H, (4.6×250 mm, Chiral Technologies, Inc., West Chester, Pa.) with amobile phase of isopropanol and supercritical CO2.

The starting materials and reagents used in preparing compoundsdescribed below are either available from commercial suppliers such asAldrich Chemical Co. (Wisconsin, USA) and Acros Organics Co. (NewJersey, USA) or were prepared by literature methods known to thoseskilled in the art.

In the Schemes below, R¹ corresponds to the moiety

shown in the various embodiments of the compounds of the invention,including in Formula (I). Compounds of the invention may be prepared asoutlined in Schemes A-G. Preparation of key intermediate A-9 isdescribed in Scheme A below. 7-Methylquinoline A-1 can be converted to7-methylquinoline-2-carbonitrile A-2 by oxidation followed bynucleophilic attack of cyanide on the activated N-oxide. Furtheroxidation of A-2 followed by treatment with POCl₃ yields4-chloro-7-methylquinoline-2-carbonitrile A-3. Metal catalyzed couplingintroduces group R₁ to give A-5, which can then be brominated at thebenzylic position giving A-6. Bromide A-6 can be displaced bynucleophile A-7 in the presence of base in a polar solvent to yield A-8.The nitrile in A-8 can subsequently be hydrolyzed to primary amide A-9using basic peroxide or under acidic conditions.Compounds A-3 to A-9 of Scheme A can be further modified by manipulationof the substitutent groups by general methods known in the art,including (but not limited to) cross coupling, oxidation, reduction,dealkylation, alkylation, acylation, and the like, and this modificationmay occur prior to or after deprotection.

An alternative route to compounds like A-9 is shown in Scheme B.Starting from A-3, bromination followed by nucleophilic displacementyields B-2, which undergoes metal catalyzed cross coupling to givecyanoquinoline A-8. Hydrolysis of the nitrile in A-8 to primary amideA-9 can be achieved using conditions similar to those in Scheme A.Additionally, the order of the nucleophilic displacement and hydrolysissteps to give A-9 can be reversed as needed. Compound B-2 of Scheme Bcan be further modified by manipulation of the substitutent groups bygeneral methods known in the art, including (but not limited to) crosscoupling, oxidation, reduction, dealkylation, alkylation, acylation, andthe like, and this modification may occur prior to or afterdeprotection.

The metal catalyzed cross coupling step can also be carried out in thepresence of the primary carboxamide in C-1 as in Scheme C for thesynthesis of compounds of general formula A-9.

Compounds of general formula D-4 can be synthesized according tosynthetic Scheme D below. Cyanoquinoline A-5 can be bis-brominated withNBS to yield gem-dibromide D-1 which can be converted to thecorresponding aldehyde D-2 with silver nitrate. Oxidation to carboxylicacid D-3 followed by amide coupling with amine A-7 yields amide D-4.Compounds D-2 to D-4 of Scheme D can be further modified by manipulationof the substitutent groups by general methods known in the art,including (but not limited to) cross coupling, oxidation, reduction,dealkylation, alkylation, acylation, and the like, and this modificationmay occur prior to or after deprotection.

Compounds of general formula E-1 can be synthesized according tosynthetic Scheme E below. Addition of organometallic reagents toaldehyde D-2 yields alcohol E-1. Compound E-1 of Scheme E can be furthermodified by manipulation of the substitutent groups by general methodsknown in the art, including (but not limited to) cross coupling,oxidation, reduction, dealkylation, alkylation, acylation, and the like,and this modification may occur prior to or after deprotection.

Keto-carboxamides F-4 can be prepared according to synthetic Scheme F.Displacement of bromide A-6 with aldehyde-containing nucleophile F-5yields cyanoquinoline F-1. Hydrolysis of the nitrile to thecorresponding carboxamide F-2 and subsequent reaction of the aldehydewith organometallic reagents yields alcohol F-3 which can be oxidized toF-4 with an oxidant such as Dess-Martin periodinane. Compounds F-1 toF-4 of Scheme F can be further modified by manipulation of thesubstitutent groups by general methods known in the art, including (butnot limited to) cross coupling, oxidation, reduction, dealkylation,alkylation, acylation, and the like, and this modification may occurprior to or after deprotection.

Preparation of key compounds such as G-9 is described in Scheme G below.Fluoro-substituted aniline G-1 can be converted to the correspondingbutanedioates G-2 by condensation with dimethyl 2-oxobutanedioate in thepresence of TsOH. Microwave irradiation of G-2 followed by treatmentwith POCl₃ yields fluoro-4-chloro-7-methylquinoline-2-carboxylate G-4.Metal catalyzed coupling introduces group R₁ to give G-5, which can thenbe brominated at the benzylic position giving G-6. Bromide G-6 can bedisplaced by succinimide in the presence of base in a polar solvent toyield G-7. Hydrolysis of the ester and subsequent coupling with ammoniumhydroxide yields primary amide G-9. Compounds G-4 to G-9 of Scheme G canbe further modified by manipulation of the substitutent groups bygeneral methods known in the art, including (but not limited to) crosscoupling, oxidation, reduction, dealkylation, alkylation, acylation, andthe like, and this modification may occur prior to or afterdeprotection.

Metal catalyzed cross couplings can be carried out with bromide A-6 andarylbornic acids as in Scheme H for the synthesis of compounds ofgeneral formula H-2. Compound H-1 and H-2 of Scheme H can be furthermodified by manipulation of the substitutent groups by general methodsknown in the art, including (but not limited to) cross coupling,oxidation, reduction, dealkylation, alkylation, acylation, and the like,and this modification may occur prior to or after deprotection.

Compounds of general formula I-6 can be synthesized according to SchemeI. Metal catalyzed cross coupling of dichloride I-1 affords I-3 afterhydrolysis of the nitrile to the methyl ester. Chloride I-3 can be crosscoupled with vinyl trifluoroborate salts to yield styrenly compoundsI-4. Hydroboration of the vinyl substituent and subsequent crosscoupling with aryl or heteroaryl halides yields compound I-5. Aminolysisof the ester affords I-6. Compounds I-2 to I-6 of Scheme I can befurther modified by manipulation of the substitutent groups by generalmethods known in the art, including (but not limited to) cross coupling,oxidation, reduction, dealkylation, alkylation, acylation, and the like,and this modification may occur prior to or after deprotection.

Example 1.1 Synthesis of4-(4-fluorophenyl)-7-methylquinoline-2-carboxamide (1-7)7-Methylquinoline N-oxide (1-2)

7-Methylquinoline (1-1, 240 g, 1.7 mol, 1.0 equiv) was dissolved inmethylene chloride (5 L, 0.34 M). 3-Chloroperoxybenzoic acid (488 g, 2.2mol, 1.3 equiv) was added portionwise with cooling so that the reactiontemperature did not rise above 34° C. After stirring for 1 h, thereaction mixture was quenched with 2L of 1N aqueous NaOH and the productwas extracted with methylene chloride. The combined organic layers werewashed with saturated aqueous sodium bicarbonate, dried over MgSO₄ andfiltered. Heptane was added and the organic layer was evaporated todryness, giving 246 g of 7-methylquinoline N-oxide (1-2) as a pink solidthat was carried on without further purification. LRMS m/z (M+H)⁺ 160.1found, 160.2 required.

7-Methylquinoline-2-carbonitrile (1-3)

To a solution of 7-methylquinoline N-oxide (1-2, 246 g, 1.54 mol, 1.0equiv) in methylene chloride (5 L, 0.31 M) was added TMS-CN (414 ml, 3.1mol., 2 equiv.) followed by dimethylcarbamoyl chloride (284 ml, 3.1 mol.2 equiv), and the resulting mixture was stirred at room temperatureovernight. The solution was quenched with saturated sodium bicarbonate,diluted with water, and extracted with dichloromethane. The combinedorganic layers were dried over MgSO₄, filtered and the solvent removedto give 260 g of crude material which was recrystallized from methanolto give 186 g of 7-methylquinoline-2-carbonitrile (1-3) in two crops.LRMS m/z (M+H)⁺ 169.1 found, 169.2 required.

7-Methylquinoline-2-carbonitrile N-oxide (1-4)

7-Methylquinoline-2-carbonitrile (181 g, 1.1 mol, 1.0 equiv.) wasdissolved in dichloromethane (3.3 L, 0.3 M). m-Chloroperbenzoic acid(500 g, 2.9 mol, 2.6 equiv) was added and the reaction mixture washeated to 40° C. After 3 hr mCPBA (7 g, 40 mmol, 0.04 equiv.) was addedand the mixture was allowed to stir overnight at room temperature. Themixture was extracted with 3 L of 1N NaOH aq., washed twice with 20 mlof dichloromethane and the combined organic phases were washed with DIwater then dried over MgSO₄. The organics were filtered and the solventwas removed to give 192 g of 7-methylquinoline-2-carbonitrile N-oxide(1-4). LRMS m/z (M+H)⁺ 185.2 found, 185.2 required.

4-Chloro-7-methylquinoline-2-carbonitrile (1-5)

7-Methylquinoline-2-carbonitrile N-oxide (1-4, 5.3 g, 28.8 mmol, 1.0equiv.) was dissolved in CHCl₃ (80 ml, 0.36 M), and POCl₃ was added(16.09 ml, 173 mmol, 6.0 equiv.). The mixture was heated to 70° C.overnight, quenched onto crushed ice and extracted three times withdichloromethane. The combined organic layers were washed with waterfollowed by saturated aqueous sodium bicarbonate, dried over MgSO₄,filtered and the solvent was removed to yield crude yellow solid.Recrystallization from heptane/EtOAc gave 95 g of4-chloro-7-methylquinoline-2-carbonitrile (1-5). LRMS m/z (M+H)⁺ 203.2found, 203.6 required.

4-(4-Fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6)

4-Chloro-7-methylquinoline-2-carbonitrile (1-5, 2.47 g, 12.2 mmol, 1.0equiv.), 4-fluorophenylboronic acid (2.05 g, 14.63 mmol, 1.2 equiv.),Pd(PPh₃)₄ (0.7 g, 0.61 mmol, 0.05 equiv), and 1M aqueous Na₂CO₃ (12.2ml, 2.39 mmol) was added into 1,4-dioxane (40 mL). The mixture wasdegassed and stirred at 100° C. for 16 hours, until disappearance of thestarting material. The mixture was cooled, saturated aqueous sodiumhydrogen carbonate (2 mL) was added and the mixture was extracted withethyl acetate (2×50 mL). The combined organic fractions were washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated underreduced pressure. The residue was treated with 50 ml of MeOH, stirredvigorously at rt for 1 h, the mixture was filtered and washed with MeOH.The solid was collected and dried under vacuum. The filtrate wasconcentrated and retrated with MeOH to get a second crop of white solidthat was combined to the first to give 2.75 g of4-(4-fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6). LRMS m/z(M+H)⁺ 263.3 found, 263.3 required.

4-(4-Fluorophenyl)-7-methylquinoline-2-carboxamide (1-7)

4-(4-Fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6, 25 mg, 0.095mmol, 1.0 equiv.) was dissolved in acetone (2.3 mL)/water (1.5 mL) andsodium percarbonate (79.0 mg, 0.477 mmol, 5.0 equiv) was added. Theresulting mixture was stirred at 50° C. for 1 hour. The mixture wascooled and concentrated. The crude residue was purified by reverse phaseHPLC (H₂O/ CH₃CN gradient w/ 0.1% TFA modifier). Fractions containingproduct were pooled and treated with Na₂CO₃. The resulting mixture wasextracted with CHCl₃. The combined organic layers were dried (MgSO₄),filtered, and concentrated to afford4-(4-fluorophenyl)-7-methylquinoline-2-carboxamide (1-7). LRMS m/z(M+H)⁺ 280.9 found, 281.3 required.

Example 1.2 Synthesis of4-(2,6-dichloro-4-fluorophenyl)quinoline-2-carboxamide (1-9)4-(2,6-Dichloro-4-fluorophenyl)quinoline-2-carboxamide (1-9)

4-Bromoquinoline-2-carboxamide (1-8, 50.0 mg, 0.199 mmol, 1.0 equiv.),(2,6-dichloro-4-fluorophenyl)boronic acid (77.0 mg, 0.398 mmol, 2.0equiv.), cesium carbonate (130.0 mg, 0.398 mmol, 2.0 equiv), Pd(OAc)₂(2.2 mg, 0.01 mmol, 0.05 equiv.), DPPF (11.0 mg, 0.020 mmol, 0.1 equiv.)and copper(I) chloride (19.7 mg, 0.199 mmol, 1.0 equiv.) were added intoDMF (1.0 mL). The mixture was stirred at 100° C. overnight. Aftercooling, aqueous sodium hydrogen carbonate (saturate, 2.0 mL) was addedand the mixture was extracted with dichloromethane (2×5 mL). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reverse phaseHPLC (H₂O/ CH₃CN gradient w/ 0.1% TFA modifier) to afford4-(2,6-dichloro-4-fluorophenyl)quinoline-2-carboxamide (1-9, 6.20 mg,9.8%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ 8.281 (s, 1H);8.200-8.226 (m, 1H); 8.175 (br s, 1H); 7.801-7.843 (m, 1H); 7.601-7.637(m, 2H); 7.137-7.183 (m, 2H); 6.140 (br s, 1H). LRMS m/z (M+H)⁺ 319.0found, 319.0 required.

The following compounds have been prepared according to proceduressimilar to those in Scheme 1.1 and 1.2 selecting the appropriatequinoline derivative and boronic acid derivative and provide examples ofcompounds in the invention.

TABLE 1 Exact Mass Example Structure IUPAC Name [M + H]⁺ 1-10

4-[4- (difluoromethoxy)phe- nyl]quinoline-2- carboxamide Calc'd 315.1,Found 315.1 1-11

4-cyclopent-1-en-1- ylquinoline-2- carboxamide (TFA salt) Calc'd 466.07,Found 466.07 1-12

4-(1-methyl-1H- pyrazol-4- yl)quinoline-2- carboxamide Calc'd 253.1,Found 253.1 1-13

4-(4-methylthiophen- 3-yl)quinoline-2- carboxamide Calc'd 269.1, Found267.07 1-14

4-(5-methyl-1-phenyl- 1H-pyrazol-4- yl)quinoline-2- carboxamide Calc'd329.1, Found 329.1 1-15

4-(4- bromophenyl)quinoline- 2-carboxamide Calc'd 327.0, Found 327.01-16

4-(2- bromophenyl)quinoline- 2-carboxamide Calc'd 327.0, Found 327.01-17

4-(4-chloro-2- methylphenyl)quinoline- 2-carboxamide Calc'd 297.1, Found297.08 1-18

4-(4-chloro-2- fluorophenyl)quinoline- 2-carboxamide Calc'd 301.1, Found301.05 1-19

4-(2-chloro-4- fluorophenyl)quinoline- 2-carboxamide Calc'd 301.1, Found301.05 1-20

4-(2-fluoro-4- methoxyphenyl)quino- line-2-carboxamide Calc'd 297.1,Found 297.1 1-21

4-(2-fluoro-4- methylphenyl)quinoline- 2-carboxamide Calc'd 281.1, Found281.1 1-22

4-(1-phenyl-1H- pyrazol-4- yl)quinoline-2- carboxamide Calc'd 315.1,Found 315.1 1-23

4-(2-cyano-4- methyphenyl)quinoline- 2-carboxamide Calc'd 288.1, Found288.1 1-24

4-(4- fluorophenyl)quinoline- 2-carboxamide Calc'd 267.1, Found 267.11-25

7-methyl-4-(4- methylphenyl)quinoline- 2-carboxamide Calc'd 277.1, Found277.0 1-26

4-(4-methoxyphenyl)- 7-methylquinoline-2- carboxamide Calc'd 293.1,Found 293.0 1-27

4-(2-chlorophenyl)-7- methylquinoline-2- carboxamide Calc'd 297.1, Found297.0 1-28

4-(2-fluorophenyl)-7- methylquinoline-2- carboxamide Calc'd 281.1, Found281.0 1-29

4-(4-cyanophenyl)-7- methylquinoline-2- carboxamide Calc'd 288.1, Found287.9

Example 2.1 Synthesis of4-(4-fluorophenyl)-7-((3-methyl-2,5-dioxoimidazolidin-1-yl)methyl)quinoline-2-carboxamide(2-3) 7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1)

4-(4-Fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6, 450 mg, 1.7mmol, 1.0 equiv) was dissolved in carbon tetrachloride (8.5 mL). NBS(310 mg, 1.7 mmol, 1.0 equiv) and AIBN (8 mg, 0.05 mmol, 0.03 equiv)were added and the mixture was refluxed overnight. The mixture was thencooled to room temperature and the white precipitate was filtered off togive 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1).LRMS m/z (M+H)⁺ 342.7 found, 342.0 required.

4-(4-Fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carbonitrile(2-2)

7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 50.0mg, 0.147 mmol, 1.0 equiv.), 1-methylimidazolidine-2,4-dione (18.4 mg,0.161 mmol, 1.1 equiv.) and cesium carbonate (95.0 mg, 0.293 mmol, 2.0equiv.) were combined into 1.0 ml of DMF. The resulting mixture wasstirred at ambient temperature for 16 hours. The solid was filtered andthe filtrate was purified by reverse phase HPLC (H₂O/ CH₃CN gradient w/0.1% TFA modifier) to afford4-(4-fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carbonitrile(2-2, 48.0 mg, 87.0%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ8.205 (d, J=1.09 Hz, 1H); 7.941 (d, J=8.79 Hz, 1H); 7.681 (dd, J₁=8.79Hz, J₂=1.83 Hz, 1H); 7.647 (s, 1H); 7.454-7.503 (m, 2H); 7.251-7.309 (m,2H); 4.935 (s, 2H); 4.049 (s, 2H); 3.057 (s, 3H). LRMS m/z (M+H)⁺375.1found, 375.1 required.

4-(4-Fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carboxamide(2-3)

4-(4-Fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carbonitrile(2-2, 44.9 mg, 0.120 mmol, 1.0 equiv.) was dissolved in acetone (1.5mL)/water (0.75 mL) and sodium percarbonate (188.0 mg, 0.600 mmol, 5.0equiv) was added. The resulting mixture was stirred at 50° C. for twohours. The mixture was cooled and poured over aqueous NH₄Cl (1.0 mL),extracted with ethyl acetate (3×5.0 mL), dried over MgSO₄, filtered andconcentrated. The crude residue was purified by reverse phase HPLC (H₂O/CH₃CN gradient w/ 0.1% TFA modifier) to afford4-(4-fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carboxamide(2-3, 35.3 mg, 75.0%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ8.498 (br s, 1H); 8.221 (d, J=1.29 Hz, 1H); 8.180 (s, 1H); 7.947 (d,J=8.60 Hz, 1H); 7.672 (dd, J₁=8.79 Hz, J₂=1.83 Hz, 1H); 7.532 (br s,1H); 7.462-7.512 (m, 2H); 7.219-7.276 (m, 2H); 4.918 (s, 2H); 3.985 (s,2H); 3.040 (s, 3H). LRMS m/z (M+H)⁺ 393.1 found, 393.1 required.

Example 2.2 Synthesis of7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide(2-7) 7-(Bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4)

4-Chloro-7-methyl-2-quinolinecarbonitrile (1-5, 57 g, 0.37 mol, 1.0equiv.), NBS (75 g, 0.42 mol, 1.14 equiv.) and benzoyl peroxide (0.8 g,3.3 mmol, 0.01 equiv.) were stirred in CH₃CN (30 ml, 12.3 M) at roomtemperature. After 16 h, the solvent was removed and the residue waspartitioned between AcOEt and water, the organic layer was washed withwater, dried over MgSO₄ and filtered. After removal of the solvent, theresidue was recrystallized from methanol to give 60 g of desired7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4). LRMS m/z (M+H)⁺283.1 found, 282.9 required.

4-Chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile(2-5)

To a room temperature solution of succinimide (4.22 g, 42.6 mmol, 1.2equiv.) in anhydrous acetonitrile (89 mL, 0.4 M) was added Hunig's base(12.4 ml, 71.0 mmol, 2.0 equiv.) and7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 10.0 g, 35.5mmol). The resulting mixture was warmed in the microwave to 100° C. for1 h. The reaction was then cooled to 0° C. and a precipitate formed. Thesolids were then collected by vacuum filtration and washed with coldacetonitrile to afford4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile(2-5) which was taken to the next step without further purification.LRMS m/z (M+H)⁺ 300.2 found, 300.0 required.

7-[(2,5-Dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile(2-6)

To a room temperature solution of 4-fluorophenylboronic acid (5.96 g,42.6 mmol, 1.2 equiv.) in dioxane:water (10:1, 177 mL, 0.2 M) was addedsodium bicarbonate (5.96 g, 71.0 mmol, 2.0 equiv.),4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile(2-5, 10.6 g, 35.5 mmol), and Pd(PPh₃)₄ (4.1 g, 3.55 mmol, 0.1 equiv.).The resulting mixture was warmed to 100° C. for 4 hr. The reaction wasthen cooled to 0° C. and a precipitate formed. The solids were thencollected by vacuum filtration and washed with water and coldacetonitrile to afford7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile(2-6) which was taken to the next step without further purification. ¹HNMR (400 MHz, CDCl₃): δ 8.115 (d, J=1.10 Hz, 1H); 7.897 (d, J=8.79 Hz,1H); 7.655 (dd, J₁=8.79 Hz, J₂=1.83 Hz, 1H); 7.603 (s, 1H); 7.439-7.475(m, 2H); 7.243-7.286 (m, 2H); 4.909 (s, 2H); 2.796 (s, 4H). LRMS m/z(M+H)⁺ 360.3 found, 360.1 required.

7-[(2,5-Dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carboxamide(2-7)

7-[(2,5-Dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile(2-6, 12.8 g, 35.5 mmol, 1.0 equiv.) was dissolved in acetone (473mL)/water (237 mL) and sodium percarbonate (55.7 g, 178 mmol, 5.0 equiv)was added. The resulting mixture was stirred at 50° C. for 1.5 hours.The mixture was cooled and poured over aqueous NH₄Cl (saturated, 250mL), extracted with ethyl acetate (3×200 mL), dried over Na₂SO₄,filtered and concentrated to afford7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carboxamide(2-7, 5.5 g, 41% over 3 steps) as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ 8.216 (s, 1H); 8.156 (s, 1H); 8.091 (br s, 1H); 7.908 (d,J=8.69 Hz, 1H); 7.614 (dd, J₁=8.79 Hz, J₂=1.71 Hz, 1H); 7.470-7.498 (m,2H); 7.211-7.262 (m, 2H); 5.668 (br s, 1H); 4.902 (s, 2H); 2.776 (s,4H). LRMS m/z (M+H)⁺ 378.3 found, 378.1 required.

The following compounds have been prepared according to proceduressimilar to those found in Scheme 2.1 and 2.2 selecting the appropriatequinoline derivative, nucleophile, and boronic acid derivative andprovide examples of compounds in the invention.

TABLE 2 Exact Mass Example Structure IUPAC Name [M + H]⁺ 2-8

7-[(2,5- dioxoimidazolidin-1- yl)methyl]-4-(4- fluorophenyl)quinoline-2-carboxamide Calc'd 379.1, Found 379.1 2-9

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-4-(4- fluorophenyl)quinoline-2-carbonitrile Calc'd 360.1, Found 360.3 2-10

7-[(4,4-dimethyl-2,6- dioxopiperidin-1- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 420.2, Found 420.2 2-11

7-[(5,5-dimethyl-2,4- dioxo-1,3-oxazolidin-3- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 408.1, Found 408.1 2-12

7-[(4,4-dimethyl-2,6- dioxopiperidin-1- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carbonitrile Calc'd 402.2, Found 402.2 2-13

4-(4-fluorophenyl)-7- [(3-methyl-2,5-dioxo-3- phenylpyrrolidin-1-yl)methyl]quinoline-2- carboxamide Calc'd 468.2, Found 468.2 2-14

7-[(3-ethyl-3-methyl- 2,5-dioxopyrrolidin-1- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 420.2, Found 420.2 2-15

4-(4-fluorophenyl)-7- [(3,4,4-trimethyl-2,5- dioxoimidazolidin-1-yl)methyl]quinoline-2- carboxamide Calc'd 421.2, Found 421.2 2-16

7-[(4,4-dimethyl-2,5- dioxoimidazolidin-1- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 407.2, Found 407.2 2-17

7-[(2,4-dioxo-1,3- oxazolidin-3- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carbonitrile Calc'd 362.1, Found 362.1 2-18

7-[(1,3-dioxo-2- azaspiro[4.4]non-2- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 432.2, Found 432.2 2-19

4-(4-fluorophenyl)-7- [(3-methyl-2,5- dioxoimidazolidin-1-yl)methyl]quinoline-2- carbonitrile Calc'd 375.1, Found 375.1 2-20

7-[(3,3-dimethyl-2,5- dioxopyrrolidin-1- yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 406.2, Found 406.2 2-21

7-[(2,6-dioxopiperidin- 1-yl)methyl]-4-(4- fluorophenyl)quinoline-2-carboxamide Calc'd 392.1, Found 392.1 2-22

4-(4-fluorophenyl)-7- [(3,3,4-trimethyl-2,5- dioxopyrrolidin-1-yl)methyl]quinoline-2- carboxamide Calc'd 420.2, Found 420.2 2-23

di-tert-butyl {[2- carbamoyl-4-(4- fluorophenyl)quinolin- 7-yl]methyl}imido- dicarbonate Calc'd 496.2, Found 496.2 2-24

4-(2-chloro-4- fluorophenyl)-7-[(2,5- dioxopyrrolidin-1-yl)methyl]quinoline-2- carboxamide Calc'd 412.1, Found 412.1 2-25

4-cylcohex-1-en-1-yl- 7-[(2,5- dioxopyrrolidin-1- yl)methyl]quinoline-2-carboxamide Calc'd 364.2, Found 364.2 2-26

4-cyclohexyl-7-[(2,5- dioxopyrrolidin-1- yl)methyl]quinoline-2-carboxamide Calc'd 366.2, Found 366.3 2-27

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-4-(4- methylcyclohex-1-en-1-yl)quinoline-2- carboxamide Calc'd 378.2, Found 378.2 2-28

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-4-(4- methylcyclohexyl)quin-oline-2-carboxamide Calc'd 380.2, Found 380.2 2-29

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-4-(4- methylphenyl)quinoline-2-carboxamide Calc'd 374.2, Found 374.2 2-30

4-(4-fluorophenyl)-7- [(2-oxo-1,3-oxazolidin- 3-yl)methyl]quinoline-2-carboxamide Calc'd 366.1, Found 366.1 2-31

4-(4-fluorophenyl)-7- [(3-methyl-2- oxoimidazolidin-1-yl)methyl]quinoline-2- carboxamide Calc'd 379.2, Found 379.2 2-32

tert-butyl {[2- carbamoyl-4-(4- fluorophenyl)quinolin-7-yl]methyl}carbamate Calc'd 396.2, Found 396.2 2-33

7-[(1,1-dioxido-1,2- thiazinan-2-yl)methyl]- 4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 414.1, Found 414.1 2-34

7-[(1,1- dioxidoisothiazolidin- 2-yl)methyl]-4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 400.1, Found 400.1 2-35

4-(4-fluorophenyl)-7- [(3-oxomorpholin-4- yl)methyl]quinoline-2-carboxamide Calc'd 380.1, Found 380.1 2-36

4-(4-fluorophenyl)-7- [(2-oxopyrrolidin-1- yl)methyl]quinoline-2-carbonitrile Calc'd 346.1, Found 346.3 2-37

4-(4-fluorophenyl)-7- [(2-oxopiperidin-1- yl)methyl]quinoline-2-carboxamide Calc'd 378.2, Found 378.2 2-38

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-4-(4- methoxyphenyl)quinoline-2-carboxamide Calc'd 390.1, Found 390.0 2-39

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-4-(2-fluoro- 4-methoxyphenyl)quinoline- 2-carboxamide Calc'd 408.1, Found 408.0

Example 3.1 Synthesis of7-((1H-benzo[d]imidazol-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide(3-2) 7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1)

Sodium percarbonate (2.98 g, 9.50 mmol, 3.0 equiv.) in water (52.8 ml)was added dropwise to a solution of7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 1.08 g,3.17 mmol, 1.0 equiv.) in acetone (106 ml) and the reaction stirred for1 hour at rt. The reaction was quenched with saturated KH₂PO₄ and themixture was extracted with EtOAc (3×). The combined organic fractionswere dried (MgSO₄), filtered, and the solvent was evaporated underreduced pressure. The crude product was purified by silica gelchromatography (120 g SiO₂, 0-100% EtOAc/hexanes) to afford7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 650 mg,57%) as a white solid. LRMS m/z (M+H)⁺359.05 found, 359.19 required.

7-((1H-Benzo[d]imidazol-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide(3-2)

Cs₂CO₃ (91 mg, 0.278 mmol, 2.0 equiv.) was added to a solution of7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 50 mg,0.139 mmol, 1.0 equiv.) and benzimidazole (18.09 mg, 0.153 mmol, 1.1equiv.) in DMF (696 μl) and the reaction stirred at rt for 2 hours. Thecrude residue was purified by reverse phase HPLC (H₂O/ CH₃CN gradient w/0.1% TFA modifier). A Waters Porapak® Rxn CX (6 cc) was conditioned withMeOH (5 mL). Fractions containing the desired product were loaded ontothe cartridge and the cartridge was washed with MeOH (10 mL). Thedesired product was eluted with 2M NH₃ in MeOH (5 mL) and the solventremoved in vacuo to afford7-((1H-Benzo[d]imidazol-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide(3-2, 23.6 mg, 43%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.40(s, 1H); 8.09 (s, 1H); 8.00-7.91 (m, 2H); 7.73-7.70 (m, 1H); 7.61-7.55(m, 3H); 7.47 (dd, J=7.2, 2.0 Hz, 1H); 7.33-7.23 (m, 4H); 5.80 (s, 2H).LRMS m/z (M+H)⁺ 397.17 found, 397.42 required.

Example 3.2 Synthesis of4-(4-fluorophenyl)-7-((5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl)methyl)quinoline-2-carboxamide(3-6) 1,1,1-Trifluoro-2-(2H-tetrazol-5-yl)butan-2-ol (3-3)

To 1,1,1-trifluorobutan-2-one (5.0 g, 39.7 mmol, 1.0 equiv) was slowlyadded trimethylsilylcyanide (4.7 g, 47.6 mmol, 1.2 equiv) and theresulting mixture stirred overnight at ambient temperature. To theresulting mixture was added water (80 mL) followed by zinc chloride (5.4g, 39.7 mmol, 1.0 equiv) and sodium azide (3.1 g, 47.1 mmol, 1.2 equiv)and the mixture was heated at 80° C. for three hours. The mixture wascooled to room temperature and the precipitate was filtered and dried invacuo to afford 1,1,1-trifluoro-2-(2H-tetrazol-5-yl)butan-2-ol (3-3) asa white solid. LRMS m/z (M+H)⁺ 197.0 found, 197.1 required.

4-(4-fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl]methyl}quinoline-2-carbonitrile(3-4)

7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 120 mg,0.35 mmol, 1.0 equiv), 1,1,1-trifluoro-2-(2H-tetrazol-5-yl)butan-2-ol(3-3, 83 mg, 0.42 mmol, 1.2 equiv) and potassium carbonate (146 mg, 1.1mmol, 3.0 equiv) were combined in DMF (1.8 mL) and stirred at ambienttemperature for 16 hours. The solids were filtered and the filtrate waspurified by reverse phase HPLC (H₂O/CH₃CN gradient w/0.1% TFA modifier)to afford4-(4-fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl]methyl}quinoline-2-carbonitrile(3-4) and4-(4-fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-1H-tetrazol-1-yl]methyl}quinoline-2-carbonitrile(3-5). ¹H NMR (3-4) (500 MHz, CDCl₃): δ 8.26 (d, J=1.7 Hz, 1H); 7.99 (d,J=8.8 Hz, 1H); 7.68 (s, 1H); 7.59 (dd, J=8.8, 1.9 Hz, 1H); 7.50-7.45 (m,2H); 7.31-7.25 (m, 2H); 6.07 (s, 2H); 2.33 (dt, J=14.3, 7.4 Hz, 1H);2.24-2.16 (m, 1H); 0.84 (t, J=7.5 Hz, 3H). LRMS m/z (M+H)′ 456.8 found,457.1 required. ¹H NMR (3-5) (500 MHz, CDCl₃): δ 8.15 (s, 1H); 7.94 (d,J=8.8 Hz, 1H); 7.65-7.61 (m, 2H); 7.48-7.44 (m, 2H); 7.30-7.24 (m, 2H);6.13 (d, J=15.0 Hz, 1H); 6.01 (d, J=15.0 Hz, 1H); 3.14-3.06 (brs, 1H);2.75 (dt, J=14.8, 7.5 Hz, 1H); 2.16 (dq, J=14.7, 7.3 Hz, 1H); 0.89 (t,J=7.4 Hz, 3H). LRMS m/z (M+H)⁺ 456.8 found, 457.1 required.

4-(4-fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl]methyl}quinoline-2-carboxamide(3-6)

4-(4-Fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl]methyl}quinoline-2-carbonitrile(3-4, 14 mg, 0.031 mmol, 1.0 equiv) was dissolved in acetone (0.5mL)/water (0.25 mL) and sodium percarbonate (48 mg, 0.15 mmol, 5.0equiv) was added. The resulting mixture was heated to 50° C. for twohours. The mixture was cooled and poured over aqueous NH₄Cl (1 mL),extracted with ethyl acetate (3×5 mL), dried over MgSO₄, filtered andconcentrated. The crude residue was purified by flash columnchromatography (SiO₂, 12 g ISCO column, 0-100% EtOAc/hexanes) to give4-(4-fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl]methyl}quinoline-2-carboxamide(3-6) as a white solid. ¹H NMR (3-6) (500 MHz, CDCl₃): δ 8.28 (s, 1H);8.17 (s, 1H); 8.06 (s, 1H); 7.99 (d, J=8.7 Hz, 1H); 7.55-7.44 (m, 3H);6.05 (s, 2H); 5.84 (s, 1H); 3.92 (s, 1H); 2.33 (dt, J=14.4, 7.4 Hz, 1H);2.20 (dt, J=14.3, 7.2 Hz, 1H); 0.84 (t, J=7.4 Hz, 3H). LRMS m/z (M+H)474.9 found, 475.1 required. ¹H NMR (3-7) (500 MHz, CD₃OD): δ 8.12 (s,1H); 8.08 (s, 1H); 7.96 (d, J=8.8 Hz, 1H); 7.64-7.55 (m, 3H); 7.34-7.29(m, 2H); 6.25 (d, J=15.1 Hz, 1H); 6.15 (d, J=15.1 Hz, 1H); 2.57 (dd,J=14.4, 7.3 Hz, 1H); 2.13 (dq, J=14.4, 7.2 Hz, 1H); 0.78 (t, J=7.4 Hz,3H). LRMS m/z (M+H)⁺ 474.7 found, 475.1 required.

Example 3.3 Synthesis of7-{[4-(cyclopropylcarbonyl)-1H-pyrazol-1-yl]methyl}-4-(4-fluorophenyl)quinoline-2-carboxamide(3-11)4-(4-Fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile(3-8)

7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 100.0mg, 0.293 mmol, 1.0 equiv.), DIEA (0.051 ml, 0.293 mmol, 1.0 equiv.),and 1-H-pyrazole-4-carbaldehyde (33.8 mg, 0.352 mmol, 1.2 equiv.) wereadded to acetonitrile (1.0 mL) in a microwave reaction vessel and theresulting mixture was irradiated with microwave at 180° C. for 30minutes. The reaction mixture was cooled and concentrated and theresidue was purified by reverse phase HPLC (H₂O/ CH₃CN gradient w/ 0.1%TFA modifier) to afford4-(4-fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile(3-8, 55.0 mg, 52.7%) as a colorless solid. LRMS m/z (M+H)⁺ 357.1 found,357.1 required.

4-(4-Fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carboxamide(3-9)

4-(4-Fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile(3-8), 51 mg, 0.143 mmol, 1.0 equiv.) was dissolved in acetone (1.0mL)/water (0.5 mL) and sodium percarbonate (225.0 mg, 0.716 mmol, 5.0equiv) was added. The resulting mixture was stirred at 50° C. for twohours. The mixture was cooled and poured over aqueous NH₄Cl (saturate,1.0 mL), extracted with Ethyl Acetate (3×5.0 mL), dried over MgSO₄,filtered and concentrated. The residue was purified by reverse phaseHPLC (H₂O/ CH₃CN gradient w/ 0.1% TFA modifier) to afford4-(4-Fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile(3-9, 40.0 mg, 74.7%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ9.879 (s, 1H); 8.262 (s, 1H); 8.056 (br s, 2H); 8.021 (br s, 2H); 7.972(d, J=8.80 Hz, 1H); 7.462-7.512 (m, 3H); 7.216-7.259 (m, 2H); 5.705 (brs, 1H); 5.589 (s, 2H). LRMS m/z (M+H)^(÷) 375.1 found, 375.1 required.

7-({4-[Cyclopropyl(hydroxy)methyl]-1H-pyrazol-1-yl}methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide(3-10)

To a 0° C. solution of4-(4-fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carboxamide(3-9, 36.0 mg, 0.0960 mmol, 1.0 equiv.) in anhydrous THF, under nitrogenwas added dropwise 0.5 M cyclopropylmagnesium bromide in THF (0.769 mL,0.385 mmol, 4.0 equiv.). The resulting mixture was stirred at 0° C. for1 hour, quenched with sat. aqueous NH₄Cl, extracted with ethyl acetate(3×5.0 mL), dried over MgSO₄, filtered and concentrated. The residue waspurified by reverse phase HPLC (H₂O/ CH₃CN gradient w/ 0.1% TFAmodifier) to afford7-({4-[cyclopropyl(hydroxy)methyl]-1H-pyrazol-1-yl}methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide(3-10, 25.0 mg, 62.4%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ8.228 (s, 1H); 8.084 (br s, 1H); 7.995 (s, 1H); 7.929 (d, J=8.81 Hz,1H); 7.625 (s, 1H); 7.515 (s, 1H); 7.442-7.506 (m, 3H); 7.206-7.249 (m,2H); 5.777 (br s, 1H); 5.526 (s, 2H); 4.044 (d, J=8.48 Hz, 1H);1.185-1.258 (m, 1H); 0.599-0.638 (m, 2H); 0.331-0.454 (m, 2H). LRMS m/z(M+H)⁺ 417.2 found, 417.2 required.

7-{[4-(Cyclopropylcarbonyl)-1H-pyrazol-1-yl]methyl}-4-(4-fluorophenyl)quinoline-2-carboxamide(3-11)

To a room temperature solution of7-({4-[cyclopropyl(hydroxy)methyl]-1H-pyrazol-1-yl}methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide(3-10, 22 mg, 0.053 mmol, 1.0 equiv.) in methylene chloride (1.0 mL) wasadded Dess-Martin Periodinane (67.2 mg, 0.158 mmol, 3.0 equiv.) and themixture was stirred at room temperature overnight. Aqueous Na₂S₂O₃(saturate, 2.0 mL) and aqueous sodium hydrogen carbonate (saturate, 5.0mL) were added and the mixture was extracted with ethyl acetate (3×5mL). The combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated. The residue was purified by reversephase HPLC (H₂O/ CH₃CN gradient w/ 0.1% TFA modifier) to afford7-{[4-(cyclopropylcarbonyl)-1H-pyrazol-1-yl]methyl}-4-(4-fluorophenyl)quinoline-2-carboxamide (3-11, 3.30 mg, 15.1%) as a colorless solid. ¹H NMR(400 MHz, CDCl₃): δ 8.239 (s, 1H); 8.179 (br s, 1H); 8.088 (s, 1H);8.039 (s, 1H); 8.017 (s, 1H); 7.965 (d, J=8.81 Hz, 1H); 7.466-7.510 (m,3H); 7.219-7.263 (m, 2H); 6.369 (br s, 1H); 5.585 (s, 2H); 2.283-2.345(m, 1 II); 1.187-1.225 (m, 2H); 0.958-1.004 (m, 2H). LRMS m/z (M+H)⁺415.2 found, 415.2 required.

Example 3.44-(o-Tolyl)-7-((4-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-1H-1,2,3-triazol-1-yl)methyl)quinoline-2-carboxamide(3-15) 7-(Azidomethyl)-4-chloroquinoline-2-carbonitrile (3-12)

Sodium azide (1.690 g, 26.0 mmol, 1.3 equiv.) was added to a stirredsolution of 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 5.63g, 20.00 mmol) in 100 ml of EtOH, and the resulting slurry mixture wasrefluxed for 1 h. The mixture was cooled to rt, water (100 ml) wasadded, and the slurry was stirred at rt for 30 min. The resulting solidwas collected by filtration and air dried to afford7-(azidomethyl)-4-chloroquinoline-2-carbonitrile (3-12, 4.75 g, 97%) asa white solid. LRMS m/z (M+H)⁺ 244.1 found, 244.65 required.

(S)-2-(1-((4-Chloro-2-cyanoquinolin-7-yl)methyl)-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-yl4-nitrobenzoate (3-13)

To a solution of 7-(azidomethyl)-4-chloroquinoline-2-carbonitrile (3-12,1 g, 4.10 mmol, 1 equiv.) and (S)-3-(trifluoromethyl)pent-1-yl-3-yl4-nitrobenzoate (1.360 g, 4.51 mmol, 1.1 equiv.) in THF (20.5 mL) wasadded DIEA (3.58 ml, 20.52 mmol, 5 equiv.) and copper (I) iodide (1.172g, 6.16 mmol, 1.5 equiv.), then stirred at rt for 2 h. The reaction wasstopped by addition of saturated NH₄Cl. The resulting mixture wasextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated. The residue was treated with MeOH.The resulting solid was collected by filtration, washed with MeOH, andair dried to afford(S)-2-(1-((4-chloro-2-cyanoquinolin-7-yl)methyl)-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-yl4-nitrobenzoate (3-13, 1.58 g, 71%) as a colorless solid. LRMS m/z(M+H)⁺ 545.4 found, 545.9 required.

4-Chloro-7-((4[(2S)-(1,1,1-trifluoro-2-hydroxybutan-2-yl)]-1H-1,2,3-triazol-1-yl)methyl)quinoline-2-carboxamide(3-14)

To(S)-2-(1-((4-chloro-2-cyanoquinolin-7-yl)methyl)-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-yl4-nitrobenzoate (3-13, 1.58 g, 2.90 mmol, 1 equiv.) in acetone/H₂O (38.7ml/19.33 mL) was added sodium percarbonate (4.55 g, 14.50 mmol, 5equiv.) and the mixture was heated to 50° C. overnight. The reaction wasincomplete. Sodium percarbonate (4.55 g, 14.50 mmol, 5 equiv.) was addedand stirred for an additional 5 hr. The mixture was cooled, water wasadded, and the mixture was extracted with EtOAc. The combined organicfractions were washed with brine, dried (MgSO₄), filtered, and thesolvent was evaporated under reduced pressure to afford4-chloro-7-((4-[(2S)-(1,1,1-trifluoro-2-hydroxybutan-2-yl)]-1H-1,2,3-triazol-1-yl)methyl)quinoline-2-carboxamide(3-14, 1.09 g, 91%) as light yellow solid. LRMS m/z (M+H)⁺ 414.3 found,414.8 required.

7-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-4-(2-methylphenyl)quinoline-2-carboxamide(3-15)

4-chloro-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide(3-14, 8 mg, 0.02 mmol, 1.0 equiv.), (2-methylphenyl)boronic acid (5 mg,0.04 mmol, 2 equiv.), Pd(PPh₃)₄ (0.7 mg, 0.0006 mmol, 0.03 equiv.) and2M aqueous Na₂CO₃ (0.02 mL, 0.05 mmol, 2.5 equiv.) were suspended inDioxane (0.4 mL) and the reaction mixture was heated overnight at 100°C. The crude mixture was filtered, concentrated and purified by reversephase HPLC (H₂O/CH₃CN gradient w/ 0.1% TFA modifier) to afford7-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-4-(2-methylphenyl)quinoline-2-carboxamide(3-15). LRMS m/z (M+H)⁺ 470.1 found, 470.2 required.

Example 3.5 Synthesis of4-(5-fluoropyridin-2-yl)-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide(3-16)4-(5-Fluoropyridin-2-yl)-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide(3-16)

4-chloro-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide(3-14, 16.0 mg, 0.039 mmol, 1.0 equiv), (5-fluoropyridin-2-yl)boronicacid (22 mg, 0.097 mmol, 2.5 equiv), cesium carbonate (25 mg, 0.077mmol, 2.0 equiv), DPPF (2.1 mg, 0.004 mmol, 0.1 equiv), copper(I)chloride (3.8 mg, 0.039 mmol, 1.0 equiv) and palladium(II) acetate (0.43mg, 0.002 mmol, 0.05 equiv) were combined and purged with argon. DMF(0.4 mL) was added and the mixture was heated at 100° C. for 14 hours.The mixture was filtered purified by reverse phase HPLC (H₂O/ CH₃CNgradient w/ 0.1% TFA modifier) to afford4-(5-fluoropyridin-2-yl)-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide(3-16) as a white solid. LRMS m/z (M+H)⁴ 475.1 found, 475.2 required

The following compounds have been prepared according to proceduressimilar to those found in Scheme 2.1, 3.1, 3.2, 3.3, 3.4, and 3.5selecting the appropriate quinoline derivative, nucleophile, and boronicacid derivative and provide examples of compounds in the invention.

TABLE 3 Exact Mass Example Structure IUPAC Name [M + H]⁺ 3-17

4-(6- fluoropyridin-3- yl)-7-({4-[(1R)-1- hydroxy-1- (trifluoromethyl)propyl]-1H-1,2,3- triazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd475.2, Found 475.2 3-18

4-(2- fluorophenyl)-7- ({4-[(1S)-1- hydroxy-1- (trifluoromethyl)propyl]-1H-1,2,3- triazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd474.2, Found 474.1 3-19

4-(2- fluoropyridin-3- yl)-7-({4-[(1S)-1- hydroxy-1- (trifluoromethyl)propyl]-1H-1,2,3- triazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd475.2, Found 475.1 3-20

4-(4- chlorophenyl)-7- ({4-[(1S)-1- hydroxy-1- (trifluoromethyl)propyl]-1H-1,2,3- triazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd490.1, Found 490.0 3-21

ethyl 1-{[2- carbamoyl-4-(4- fluorophenyl)quin- olin-7-yl]methyl}-1H-pyrazol-4- carboxylate Calc'd 419.2, Found 419.2 3-22

ethyl 1-{[2- carbamoyl-4-(4- fluorophenyl)quin- olin-7-yl]methyl}- 3-(trifluoromethyl)- 1H-pyrazole-4- carboxylate Calc'd 487.1, Found 487.13-23

7-({4- [cyclopentyl(hy- droxy)methyl]-1H- pyrazol-1- yl}methyl)-4-(4-fluorophenyl)quin- oline-2- carboxamide Calc'd 445.2, Found 445.2 3-24

methyl 1-{[2- carbamoyl-4-(4- fluorophenyl)quin- olin-7-yl]methyl}-1H-pyrazole-4- carboxylate Calc'd 405.1, Found 405.1 3-25

7-[(4-bromo-1H- imidazol-1- yl)methyl]-4-(4- fluorophenyl)quin- oline-2-carboxamide Calc'd 425.0, found 425.0 3-26

methyl 1-{[2- carbamoyl-4-(4- fluorophenyl)quin- olin-7-yl]methyl}-1H-imidazole-5- carboxylate Calc'd 405.1, Found 405.1 3-27

methyl 1-{[2- carbamoyl-4-(4- fluorophenyl)quin- olin-7-yl]methyl}-1H-imidazole-4- carboxylate Calc'd 405.1, Found 405.1 3-28

1-{[2-carbamoyl- 4-(4- fluorophenyl)quin- olin-7-yl]methyl}-1H-1,2,3-triazole- 4-carboxylic acid Calc'd 392.1, Found 392.1 3-29

4-(4- fluorophenyl)-7- (1H-imidazol-1- ylmethyl)quinoline- 2-carboxamideCalc'd 347.1, Found 347.1 3-30

4-(4- fluorophenyl)-7- {[2-(1- methylethyl)-1H- imidazol-1-yl]methyl}quinoline- 2-carboxamide Calc'd 389.2, Found 389.2 3-31

4-(4- fluorophenyl)-7- [(2-methyl-1H- imidazol-1- yl)methyl]quinoline-2-carboxamide Calc'd 361.1, Found 361.1 3-32

7-[(2-chloro-1H- imidazol-1- yl)methyl]-4-(4- fluorophenyl)quin-oline-2- carboxamide Calc'd 381.1, Found 381.1 3-33

4-(4- fluorophenyl)-7- (3H-imidazo[4,5- b]pyridin-3- ylmethyl)quinoline-2-carboxamide Calc'd 398.1, Found 398.1 3-34

4-(4- fluorophenyl)-7- (1H-imidazo[4,5- b]pyridin-1- ylmethyl)quinoline-2-carboxamide Calc'd 398.1, Found 398.1 3-35

1-{[2-carbamoyl- 4-(4- fluorophenyl)quin- olin-7-yl]methyl}- 1H-benzimidazole-2- sulfonic acid Calc'd 477.1, Found 477.1 3-36

4-(4- fluorophenyl)-7- [(2-pyridin-2-yl- 1H-benzimidazol- 1-yl)methyl]quinolin- 2-carboxamide Calc'd 474.2, Found 474.2 3-37

4-(4- fluorophenyl)-7- [(2-pyridin-3-yl- 1H-benzimidazol- 1-yl)methyl]quinoline- 2-carboxamide Calc'd 474.2, Found 474.2 3-38

4-(4- fluorophenyl)-7- {[2-(2,2,2- trifluoroethyl)- 1H-benzimidazol- 1-yl]methyl}quinoline- 2-carboxamide Calc'd 480.1, Found 480.1 3-39

7-[(2-cyclopropyl- 1H-benzimidazol- 1-yl)methyl]-4-(4-fluorophenyl)quin- oline-2- carboxamide Calc'd 437.2, Found 437.2 3-40

7-[(2-cyclobutyl- 1H-benzimidazol- 1-yl)methyl]-4-(4- fluorophenyl)quin-oline-2- carboxamide Calc'd 451.2, Found 451.2 3-41

7-[(2-cyclopentyl- 1H-benzimidazol- 1-yl)methyl]-4-(4-fluorophenyl)quin- oline-2- carboxamide Calc'd 465.2, Found 465.2 3-42

4-(4- fluorophenyl)-7- [(2-methyl-1H- benzimidazol-1-yl)methyl]quinoline- 2-carboxamide Calc'd 411.2, Found 411.2 3-43

4-(4- fluorophenyl)-7- {[2-(1- methylethyl)-1H- benzimidazol-1-yl]methyl}quinoline- 2-carboxamide Calc'd 439.2, Found 439.2 3-44

4-(4- fluorophenyl)-7- ({4-[(1S)-1- hydroxy-1- (trifluoromethyl)propyl]-1H- imidazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd 473.2,Found 473.2 3-45

4-(4- fluorophenyl)-7- ({4-[(1R)-1- hydroxy-1- (trifluoromethyl)propyl]-1H- imidazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd 473.2,Found 473.2 3-46

4-(3,4- dimethoxyphenyl)- 7-({4-[1- hydroxy-1- (trifluoromethyl)propyl]-1H- imidazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd 515.2,Found 515.3 3-47

7-({4-[1-hydroxy- 1- (trifluoromethyl) propyl]-1H- imidazol-1-yl}methyl)-4-(4- methoxy-3- methylphenyl) quinoline-2- carboxamideCalc'd 499.2, Found 499.3 3-48

4-(2-fluoro-4- methoxyphenyl)- 7-({4-[1-hydroxy- 1- (trifluoromethyl)propyl]-1H- imidazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd 503.2,Found 503.2 3-49

4-(3-fluoro-4- methoxyphenyl)- 7-({4-[1-hydroxy- 1- (trifluoromethyl)propyl]-1H- imidazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd 503.2,Found 503.2 3-50

4-(2-fluoro-4- methoxyphenyl)- 7-({4-[1-hydroxy- 1- (trifluoromethyl)propyl]-1H- imidazol-1- yl}methyl)quinoline- 2-carboxamide Calc'd 503.2,Found 503.2 3-51

7-({4-[1-hydroxy- 1- (trifluoromethyl) propyl]-1H- imidazol-1-yl}methyl)-4-(4- methoxyphenyl) quinoline-2- carboxamide Calc'd 485.2,Found 485.4

Example 4.1 Synthesis of4-(4-fluorophenyl)-7-(morpholin-4-ylmethyl)quinoline-2-carboxamide (4-1)4-(4-Fluorophenyl)-7-(morpholin-4-ylmethyl)quinoline-2-carboxamide (4-1)

To a room temperature solution of7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 311.0mg, 0.895 mmol, 1.0 equiv.) in acetonitrile (10.0 mL) was addedmorphline (85.77 mg, 0.985 mmol, 1.1 equiv.) and 5.0 M aqueous NaOH(2.69 mL, 13.43 mmol, 15 equiv.), and the resulting mixture was stirredat 50° C. for 4 days. After cooling to room temperature, water (100.0mL) was added and the mixture was stirred for 30 minutes. A yellow solidwas collected via suction filtration, washed with water, dried in vacuo.The solid was purified by reverse phase HPLC (H₂O/ CH₃CN gradient w/0.1% TFA modifier) to afford4-(4-fluorophenyl)-7-(morpholin-4-ylmethyl)quinoline-2-carboxamide (4-1,291.0 mg, 80.0%) as a colorless solid. ¹H NMR (500 MHz, CDCl₃): δ 8.216(s, 1H); 8.098 (br s, 2H); 7.911 (d, J=8.54 Hz, 1H); 7.642 (d, J=8.55Hz, 1H); 7.503-7.529 (m, 2H); 7.219-7.263 (m, 2H); 5.798 (br s, 1H);3.734 (br s, 6H); 2.528 (br s, 2H). LRMS m/z (M+H)⁺ 366.2 found, 366.2required.

Example 4.2 Synthesis of4-(1-methyl-1/H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(4-9) (R)-3-(Benzylamino)-1,1,1-trifluoropropan-2-ol (4-2)

To a solution of lithium trifluoromethanesulfonate (1.43 g, 9.17 mmol)in CH₃CN (30 ml) was added (R)-(+)-3,3,3-trifluoro-1,2-epoxypropane(10.77 g, 96 mmol) slowly at −10° C. After 5 minutes benzylamine (10 ml,92 mmol) was added slowly. The mixture was allowed to warm as the bathwarmed to rt overnight. The mixture was concentrated. The crude productwas subjected to silica gel chromatography (330 g, 0-50% EtOAc/hexanes,10 minute gradient) to afford(R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (4-2, 15.9 g, 79%) as awhite solid. LRMS m/z (M+H)⁺ 220.2 calc.; 220.1 found.

(S)—N—Benzyl-2-hydroxy-((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide(4-3)

To a solution of (R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (4-2, 5g, 22.81 mmol) in CH₃CN (200 ml) was added DIEA (12 ml, 68.7 mmol),(S)-2-chloropropionic acid (2.4 ml, 27.4 mmol), then2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (16.3ml, 27.4 mmol) slowly at rt. After 2.5 hr the mixture was concentrated.The material was taken up in EtOAc and washed with saturated NaHCO₃,H₂O, and brine. The organic layer was filtered through a pad of silicagel washing with ethyl acetate then concentrated to afford(S)—N-benzyl-2-hydroxy-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide(4-3) as a clear oil which was sufficiently pure for use in the nextstep.

(2R,6R)-4-Benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (4-4)

A solution of(S)—N-benzyl-2-hydroxy-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide(4-3) in THF (200 ml) was cooled to 0° C. To this was added NaH (60%dispersion in mineral oil, 1.05 g, 26.3 mmol) portionwise as a solid.After 1 hr the cooling bath was removed and the mixture allowed to warmto rt. After an additional hour the mixture was quenched with brine. Themixture was diluted with H₂O and extracted with EtOAc (3×). The combinedorganic layers were dried (MgSO₄), filtered, and concentrated to afford(2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (4-4) as aclear oil which was sufficiently pure for use in the next step.

(2R,6R)-4-Benzyl-2-methyl-6-(trifluoromethyl)morpholine (4-5)

To a solution of(2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (4-4) wasadded 1M LAH (48 ml, 48.0 mmol) in THF slowly at rt. After the additionwas complete the mixture was heated to reflux. After 1 hr the mixturewas cooled to rt then 0° C. The mixture was slowly quenched with 2M NaOHuntil gas evolution had ceased and a fine white precipitate formed.Anhydrous MgSO₄ was added and the mixture stirred for 15 minutes Theslurry was filtered through a pad of celite washing with EtOAc thenconcentrated. The crude product was subjected to silica gelchromatography (120 g, 0-10% EtOAc/hexanes, 15 minute gradient) to givea afford (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine (4-5,4.1 g, 66% over 3 steps) as clear oil. ¹H NMR (400 MHz, CDCl₃): δ7.35-7.26 (m, 5H); 4.02 (dqd, J=10.7, 6.4, 2.5 Hz, 1H); 3.76-3.69 (m,1H); 3.60-3.48 (m, 2H); 2.89 (d, J=11.1 Hz, 1H); 2.73-2.68 (m, 1H);2.16-2.04 (m, 1H); 1.91-1.79 (m, 1H); 1.19 (d, J=6.3 Hz, 3H).

(2R,6R)-2-Methyl-6-(trifluoromethyl)morpholine hydrochloride (4-6)

To a solution of (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine(4-5, 4.1 g, 15.81 mmol) in MeOH (80 ml) was added concentrated HCl (6.6ml, 79 mmol). This mixture was transferred to a Parr bottle containing10% Pd/C (1.7 g, 1.597 mmol). The mixture was hydrogenated (45 psi)overnight. The mixture was filtered through a pad of Celite washing withMeOH then concentrated. The residue was taken up in MeOH andconcentrated (3×) to afford(2R,6R)-2-methyl-6-(trifluoromethyl)morpholine hydrochloride (4-6, 3.34g, 103%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 4.59 (bs,2H); 4.27 (bs, 2H); 3.01 (bs, 1H); 2.79 (bs, 1H); 1.33 (s, 3H).

4-Chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile(4-7)

(2R,6R)-2-Methyl-6-(trifluoromethyl)morpholine hydrochloride (4-6, 500mg, 2.432 mmol) and K₂CO₃ (739 mg, 5.35 mmol) were combined in CH₃CN (10ml) at rt. To this was added7-(bromornethyl)-4-chloroquinoline-2-carbonitrile (2-4, 753 mg, 2.68mmol) all at once as a solid then the mixture was heated to 60° C.overnight. The mixture was cooled to rt, diluted with H₂O, and extractedwith EtOAc (3×). The combined organic layers were filtered through a padof Celite washing with EtOAc then concentrated. The crude product wassubjected to silica gel chromatography (50 g, 0-10% EtOAc/hexanes, 15minute gradient) to afford4-chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile(4-7, 859, 96%) as a white foam. ¹H NMR (400 MHz, CDCl₃): δ 8.26 (d,J=8.7 Hz, 1H); 8.11 (s, 1H); 7.83 (dd, J=8.6, 1.6 Hz, 1H); 7.78 (s, 1H);4.09-4.01 (m, 1H); 3.79 (m, 3H); 2.90 (d, J=10.9 Hz, 1H); 2.73 (d,J=11.4 Hz, 1H); 2.28-2.17 (m, 1H); 2.03-1.92 (m, 1H); 1.20 (d, J=6.2 Hz,3H).

4-(1-Methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile(4-8)

4-Chloro-7-((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile(4-7, 859 mg, 2323 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(725 mg, 3.48 mmol), Pd(OAc)₂ (26 mg, 0.116 mmol), and X-Phos (111 mg,0.232 mmol) were combined in THF (10 ml). To this was added 1M K₃PO₄ (7ml, 7.00 mmol). The mixture was degassed (3× pump/N₂) then heated to 70°C. overnight. The mixture was cooled to rt, diluted with H₂O, andextracted with EtOAc (3×). The combined organic layers were filteredthrough a pad of Celite washing with EtOAc then concentrated. The crudeproduct was subjected to silica gel chromatography (100 g, 50%EtOAc/hexanes) to afford4-(1-methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile(4-8, 650 mg, 67%) as a white solid. ¹H NMR (399 MHz, CDCl₃): δ 8.22 (d,J=8.7 Hz, 1H); 8.10 (s, 1H); 7.86 (s, 1H); 7.78 (s, 1H); 7.71 (dd,J=8.7, 1.7 Hz, 1H); 7.63 (s, 1H); 4.07 (m, 3H); 3.78 (m, 3H); 2.92 (d,J=11.0 Hz, 1H); 2.75 (d, J=11.4 Hz, 1H); 2.22 (t, J=10.8 Hz, 1H); 1.97(t, J=10.8 Hz, 1H); 1.20 (d, J=6.3 Hz, 3H).

4-(1-Methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(4-9)

4-(1-Methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile(4-8, 650 mg, 1.565 mmol) was taken up in concentrated HCl (10 ml) andstirred at rt. After 3 hrs the mixture was quenched by slow addition ofit to a solution of K₂CO₃ (17 g) in 100 ml H₂O. The reaction flask wasrinsed into the quench with H₂O bringing the total volume to 150 mL H₂O.The resulting mixture was stirred at rt for 1 hr. The off-white solidwas collected by filtration, washed with H₂O, and air dried. The crudeproduct was subjected to silica gel chromatography (40 g, 100% EtOAc) toafford4-(1-methyl-1H-pyrazol-4-yl)-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(4-9, 592 mg, 87%) as a white foam. ¹H NMR (399 MHz, CDCl₃): δ 8.27-8.22(m, 2H); 8.10 (bs, 1H); 8.04 (s, 1H); 7.90 (s, 1H); 7.80 (s, 1H); 7.65(dd, J=8.7, 1.7 Hz, 1H); 5.67 (bs, 1H); 4.06 (m, 3H); 3.82-3.74 (m, 3H);2.95 (d, J=11.0 Hz, 1H); 2.77 (d, J=11.5 Hz, 1H); 2.21 (t, J=10.8 Hz,1H); 2.05 (s, 1H); 1.96 (t, J=10.8 Hz, 1H); 1.20 (d, J=6.3 Hz, 3H); LRMSm/z (M+H)⁺ 434.4 calc.; 434.3 found.

Example 4.3 Synthesis of7-((2-cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide(4-16) 1-Cyclopropyl-2-nitroethanol (4-10)

A mixture of THF (10 ml) and t-BuOH (10.00 ml) was cooled to 0° C. Tothis was added cyclopropanecarboxaldehyde (1.1 ml, 14.60 mmol) andnitromethane (1.18 ml, 21.88 mmol). After stirring 5 minutes 1M KO^(t)Bu(2.92 ml, 2.92 mmol) in THF was added slowly. During the addition awhite solid formed. The mixture was allowed to warm as the bath warmedto rt overnight. The mixture was diluted with saturated aqueous NH₄Cland extracted with CH₂Cl₂ (3×). The combined organic layers were dried(MgSO₄), filtered, and concentrated (no heat) to afford1-cyclopropyl-2-nitroethanol (4-10, 1.9 g, 99%) as a clear oil which wassufficiently pure for use in the next step. ¹H NMR (399 MHz, CDCl₃): δ4.56-4.52 (m, 2H); 3.72-3.64 (m, 1H); 2.42 (d, J=3.9 Hz, 1H); 0.99-0.90(m, 1H); 0.68-0.59 (m, 2H); 0.52-0.44 (m, 1H); 0.39-0.32 (m, 1H).

(E)-(2-Nitrovinyl)cyclopropane (4-11)

Crude 1-cyclopropyl-2-nitroethanol (4-10, 1.9 g, 14.49 mmol) was takenup in CH₂Cl₂ (20 ml) then cooled to 0° C. To this was added TFAA (2.3ml, 16.28 mmol) followed by a slow addition of TEA (4.5 ml, 32.3 mmol).The mixture was allowed to warm as the bath warmed to rt. After 3 hr themixture was filtered through a pad of silica gel washing with CH₂Cl₂.The filtrate was concentrated (no heat) to a yellow oil. The oil wastaken up in 20% Et₂O/hexanes and filtered through a pad of silica gelwashing with 20% Et₂O/hexanes. The filtrate was concentrated (no heat)to afford (E)-(2-nitrovinyl)cyclopropane (4-11, 1.49 g, 91%) as a verypale yellow oil which was sufficiently pure for use in the next step. ¹HNMR (399 MHz, CDCl₃): δ 7.14 (d, J=13.2 Hz, 1H); 6.79 (dd, J=13.2, 10.8Hz, 1H); 1.68-1.58 (m, 1H); 1.19-1.11 (m, 2H); 0.84-0.78 (m, 2H).

Ethyl 2-((1-cyclopropyl-2-nitroethyl)thio)acetate (4-12)

(E)-(2-Nitrovinyl)cyclopropane (4-11, 750 mg, 6.63 mmol) was taken up inTHF (20 mL). To this was added ethyl thioglycolate (0.88 mL, 7.98 mmol)then TEA (1.2 mL, 8.61 mmol) at rt. After stirring overnight the mixturewas concentrated. The crude product was subjected to silica gelchromatography (40 g, 0-20% EtOAc/hexanes, 10 minute gradient) to affordethyl 2-((1-cyclopropyl-2-nitroethyl)thio)acetate (4-12, 1.46 g, 94%) asa clear oil. ¹H NMR (399 MHz, CDCl₃): δ 4.73-4.58 (m, 2H); 4.21 (q,J=7.1 Hz, 2H); 3.34 (d, J=6.2 Hz, 2H); 2.93 (dt, J=9.9, 7.2 Hz, 1H);1.30 (t, J=7.1 Hz, 3H); 1.00-0.90 (m, 1H); 0.69 (dd, J=8.0, 1.6 Hz, 2H);0.47-0.36 (m, 2H).

6-Cyclopropylthiomorpholin-3-one (4-13)

Ethyl 2-((1-cyclopropyl-2-nitroethyl)thio)acetate (4-12, 1.46 g, 6.26mmol) was taken up in AcOH (30 ml). To this was added zinc powder (4093mg, 62.6 mmol) then the mixture was heated to 70° C. After stirringovernight the mixture was cooled to rt, diluted with AcOH, filteredthrough a pad of Celite washing with AcOH, and concentrated. The crudeproduct was subjected to silica gel chromatography (40 g, 0-100%EtOAc/hexanes, 10 minute gradient) to afford6-cyclopropylthiomorpholin-3-one (4-13, 355 mg, 36%) as an amber oilwhich solidified slowly under vacuum. ¹H NMR (399 MHz, CDCl₃): δ 6.65(s, 1H); 3.65 (dt, J=13.2, 4.4 Hz, 1H); 3.54-3.46 (m, 1H); 3.32 (s, 2H);2.47-2.39 (m, 1H); 0.98-0.89 (m, 1H); 0.67-0.58 (m, 2H); 0.41-0.25 (m,2H).

2-Cyclopropylthiomorpholine (4-14)

A solution of 6-cyclopropylthiomorpholin-3-one (4-13, 355 mg, 2.258mmol) in THF (10 ml) was cooled to 0° C. To this was added 2M LAH (2.3ml, 4.60 mmol) slowly. After the addition was complete the cooling bathwas removed and the mixture allowed to warm to it. After stirringovernight the mixture was cooled to 0° C. and slowly quenched with 2MNaOH until gas evolution had ceased and a fine white precipitate formed.Anhydrous Na₂SO₄ was added and the mixture stirred for 15 minutes. Theslurry was filtered through a pad of Celite washing with THF and thefiltrate concentrated to afford 2-cyclopropylthiomorpholine (4-14, 242mg, 75%) as a pale yellow oil which was used in subsequent steps as is.

7-((2-Cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile(4-15)

To a solution of crude 2-cyclopropylthiomorpholine (4-14, 100 mg, 0.698mmol) in CH₃CN (3 ml) was added K₂CO₃ (289 mg, 2.094 mmol) then7-(bromomethyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile(251 mg, 0.768 mmol) all at once as solid. The resulting mixture washeated to 60° C. overnight. The mixture was cooled to rt, diluted withEtOAc, filtered through a pad of Celite washing with EtOAc, andconcentrated. The crude product was subjected to silica gelchromatography (25 g, 0-100% EtOAc/hexanes, 10 minute gradient) toafford7-((2-Cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile(4-15, 123 mg, 45%) as a light orange foam. ¹H NMR (399 MHz, CDCl₃): δ8.19 (d, J=8.7 Hz, 1H); 8.09 (s, 1H); 7.85 (s, 1H); 7.77 (s, 1H); 7.71(d, J=8.8 Hz, 1H); 7.61 (s, 1H); 4.07 (s, 3H); 3.85-3.70 (m, 2H); 3.16(dd, J=11.6, 2.7 Hz, 1H); 3.01 (d, J=11.6 Hz, 1H); 2.83 (ddd, J=13.4,10.6, 2.7 Hz, 1H); 2.61-2.53 (m, 1H); 2.45-2.34 (m, 2H); 2.20-2.13 (m,1H); 0.88-0.80 (m, 1H); 0.61-0.44 (m, 2H); 0.36-0.27 (m, 1H); 0.23-0.16(m, 1H).

7-((2-Cyclopropylthiomorpholino)methyl)-4-(1-methyl)-1H-pyrazol-4-yl)quinoline-2-carboxamide(4-16)

7-((2-Cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile(4-15, 40 mg, 0.103 mmol) was taken up in concentrated HCl (0.6 ml) andstirred at rt. After 4 hr the mixture was quenched by slow addition ofit to saturated NaHCO₃. The resulting mixture was extracted with CH₂Cl₂(3×). The combined organic layers were filtered through a pad of Celitewashing with CH₂Cl₂ then concentrated. The crude product was subjectedto silica gel chromatography (25 g, 100% EtOAc) to afford7-((2-cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide(4-16, 28 mg, 67%) as an off-white foam. ¹H NMR (399 MHz, CDCl₃): δ 8.22(m, 2H); 8.10 (s, 1H); 8.04 (s, 1H); 7.89 (s, 1H); 7.80 (s, 1H); 7.65(d, J=8.7 Hz, 1H); 5.62 (s, 1H); 4.05 (s, 3H); 3.87-3.68 (m, 2H); 3.19(d, J=11.6 Hz, 1H); 3.04 (d, J=11.6 Hz, 1H); 2.91-2.79 (m, 1H);2.61-2.53 (m, 1H); 2.46-2.35 (m, 2H); 2.23-2.15 (m, 1H); 0.88-0.79 (m,1H); 0.60-0.46 (m, 2H); 0.36-0.27 (m, 1H); 0.26-0.18 (m, 1H). LRMS m/z(M+H)⁺ 408.5 calc.; 408.3 found.

Example 4.4 Synthesis of 4-(4-fluorophenyl)-7-(((2S)-2-methyl-5(R orS)-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carboxamide (4-22)Tert-butyl((2S)-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)carbamate(4-17)

To a stirred solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate(3.15 g, 18.18 mmol), and DCM (91 ml) was added2-amino-3,3,3-trifluoropropan-1-ol (2.230 g, 17.28 mmol). Stirred atambient temperature for 10 minutes and then added sodiumtriacetoxyborohydride (5.78 g, 27.3 mmol). The mixture was stirredovernight. The reaction was diluted with DCM and then washed with 1 NNaOH, brine dried over MgSO₄, filtered and the solvent removed toprovide 4.0 grams of tert-butyl((2S)-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)carbamateas a colorless oil that was used without further purification. LRMS m/z(M+H)⁺ 287.3 found, 287.3 required.

Tert-butyl((2S)-1-((1,1,1-trifluoro-3-iodopropan-2-yl)amino)propan-2-yl)carbamate(4-18)

To a stirred mixture of triphenylphosphine (resin bound, 1.88 mmol/gram,7.70 g, 14.67 mmol) in DCM (48.9 ml) was added iodine (3.72 g, 14.67mmol). Stirred for 15 minutes. Added imidazole (1.332 g, 19.56 mmol) andstirred for 15 minutes, then added tert-butyl((2S)-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)carbamate(2.8 g, 9.78 mmol), dissolved in DCM (48 ml), and then the mixture washeated to reflux for 3 hours. Cooled to room temperature and filteredthrough celite. The resulting solution was washed with saturated sodiumthiosulfate, dried over MgSO₄, filtered and concentrated. The cruderesidue was purified by column chromatography on silica gel eluting withhexanes to EtOAc to provide tert-butyl((2S)-1-((1,1,1-trifluoro-3-iodopropan-2-yl)amino)propan-2-yl)carbamateas a colorless oil. LRMS m/z (M+H)⁺ 397.1 found, 397.2 required.

(2 S)—N1-(1,1,1-trifluoro-3-iodopropan-2-yl)propane-1,2-diamine2,2,2-trifluoroacetate (4-19)

To a stirred solution of tert-butyl((2S)-1-((1,1,1-trifluoro-3-iodopropan-2-yl)amino)propan-2-yl)carbamate(1.6 g, 4.04 mmol) and DCM (8.08 ml) was added TFA (6.22 ml, 81 mmol).Stirred for 1 hour at ambient temperature and then the solution wasconcentrated. The residue was azeotroped with toluene (3×10 ml) toprovide (2S)—N1-(1,1,1-trifluoro-3-iodopropan-2-yl)propane-1,2-diamine2,2,2-trifluoroacetate as a yellow oil that was used without furtherpurification. LRMS m/z (M+H)⁺ 297.1 found, 297.0 required.

4-(4-Fluorophenyl)-7-((2S)-2-methyl-5-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carbonitrile(4-21)

(2S)—N1-(1,1,1-trifluoro-3-iodopropan-2-yl)propane-1,2-diamine2,2,2-trifluoroacetate (1.66 g, 4.05 mmol) and acetonitrile (20.24 ml)were combined and then added potassium carbonate (1.678 g, 12.14 mmol).The mixture was stirred for 4 hours at ambient temperature and then wasfiltered through a celite pad and concentrated to ⅓ of original volume.

To the solution of (2S)-2-methyl-5-(trifluoromethyl)piperazine (4-20)was added DMA (1.76 ml), DIEA (0.614 ml, 3.52 mmol) followed by7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (300 mg,0.879 mmol). The reaction was heated to 50° C. for 4 hours. The reactionwas diluted with EtOAc and then washed with H₂O, brine, dried (MgSO₄)and concentrated. The residue was purified by column chromatography onsilica gel eluting with hexanes to EtOAc to provide4-(4-fluorophenyl)-7-(((2S)-2-methyl-5-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carbonitrileas a colorless solid. LRMS m/z (M+H)⁺ 429.2 found, 429.4 required.

4-(4-Fluorophenyl)-7-(((2S)-2-methyl-5(R orS)-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carboxamide (4-22)

4-(4-fluorophenyl)-7-(((2S)-2-methyl-5-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carbonitrile(275 mg, 0.642 mmol) was dissolved in conc HCl (2636 μl, 32.1 mmol) andthen stirred at ambient temperature for 4 hours. The yellow solution wasslowly poured into aq potassium carbonate (12.8 ml, 5M, 64 mmol) at 0°C. The resulting mixture was extracted with chloroform. The organicportion was dried over MgSO₄ and concentrated. The residue was purifiedby preparative HPLC Chiralpak AD, 5 cm×500 cm, 50 ml/min eluting with20% IPA/hexanes +0.1% Et□NH, to provide isomers A and B of4-(4-fluorophenyl)-7-(((2S)-2-methyl-5(R orS)-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carboxamide ascolorless foams. Isomer A, LRMS m/z (M+H)⁺ 447.3 found, 447.4 required¹H NMR (500 MHz, CDCl₃):8.22 (1H, s), 8.10 (2H, d, J=12.11 Hz), 7.91(1H, d, J=8.69 Hz), 7.65 (1H, dd, J=8.72, 1.66 Hz), 7.52 (2H, dd,J=8.44, 5.36 Hz), 5.64 (1H, s), 3.89 (1H, d, J=13.93 Hz), 3.77 (1H, d,J=13.94 Hz), 3.39-3.34 (1H, m), 3.08-3.04 (1H, m), 2.94-2.87 (2H, m),2.73 (1H, dd, J=11.54, 8.93 Hz), 2.60 (1H, dd, J=11.55, 3.62 Hz), 1.17(3H, d, J=6.41 Hz).

Isomer B, LRMS m/z (M+H)⁺ 447.3 found, 447.4 required

¹H NMR (500 MHz, CDCl₃):8.21 (1H, s), 8.10 (2H, d, J=14.50 Hz), 7.91(1H, d, J=8.70 Hz), 7.65 (1H, d, J=8.75 Hz), 7.52 (2H, dd, J=8.22, 5.34Hz), 5.74 (1H, s), 3.89 (1H, d, J=13.95 Hz), 3.77 (1H, d, J=13.95 Hz),3.37 (1H, t, J=7.88 Hz), 3.09-2.98 (2H, m), 2.91 (2H, d, J=11.86 Hz),2.73 (1H, t, J=10.19 Hz), 2.60 (1H, dd, J=11.55, 3.52 Hz), 1.17 (3H, d,J=6.36 Hz).

Chiral HPLC Analytical data: 1 ml/min 20% IPa/hexanes, 4.6×250 mm ADcolumn

Isomer A: 7.63 minutes

Isomer B: 8.63 minutes

The following compounds have been prepared according to proceduressimilar to those found in Scheme 4.1, 4.2, 4.3, and 4.4 selecting theappropriate quinoline derivative, nucleophile, and boronic acidderivative and provide examples of compounds in the invention.

TABLE 4 Exact Mass Example Structure IUPAC Name [M + H]⁺ 4-23

methyl 1-{[2- carbamoyl-4-(4- fluorophenyl)quino- lin-7-yl]methyl}-L-prolinate Calc'd 408.2, Found 408.2 4-24

7-{[(2S)-2- carbamoylpyrrolidin- 1-yl]methyl}-4- (4- fluorophenyl)quino-line-2-carboxamide Calc 393.2, Found 393.2 4-25

7-[(3,3- difluoropyrrolidin- 1-yl)methyl]-4-(4- fluorophenyl)quino-line-2-carboxamide Calc 386.1, Found 386.1 4-26

4-(4-fluorophenyl)- 7-{[(3R)-3- fluoropyrrolidin-1- yl]methyl}quinoline-2-carboxamide Calc'd 368.2, Found 368.2 4-27

4-(4-fluorophenyl)- 7-{[2- (trifluoromethyl) pyrrolidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 418.2, Found 418.2 4-28

4-(4-fluorophenyl)- 7-[(3-oxopiperazin- 1- yl)methyl]quinoline-2-carboxamide Calc'd 379.2, Found 379.2 4-29

4-(4-fluorophenyl)- 7- {[methoxy(methyl) amino]methyl}quin- oline-2-carboxamide Calc'd 340.1, Found 340.1 4-30

4-(4-fluroophenyl)- 7-{[(2- methoxyethyl)(meth- yl)amino]methyl}quinoline-2- carboxamide Calc'd 368.2, Found 368.2 4-31

7-{[(2-amino-2- oxoethyl)(methyl) amino]methyl}-4-(4-fluorophenyl)quino- line-2-carboxamide Calc'd 367.2, Found 367.2 4-32

7-{[(2S)-2- cyanopyrrolidin-1- yl]methyl}-4-(4- fluorophenyl)quino-line-2-carboxamide Calc'd 375.2, Found 375.2 4-33

4-(4-fluorophenyl)- 7-{[(3S)-3- methoxypyrrolidin- 1-yl]methyl}quinoline- 2-carboxamide Calc'd 380.2, Found 380.2 4-34

7-{[3- (dimethylamino) pyrrolidin-1- yl]methyl}-4-(4-fluorophenyl)quino- line-2-carboxamide Calc'd 393.2, Found 393.2 4-35

7-{[3- (acetylamino)pyrroli- din-1-yl]methyl}- 4-(4- fluorophenyl)quino-line-2-carboxamide Calc'd 407.2, Found 407.2 4-36

7-[(2-carbamoyl-4- hydroxypyrrolidin- 1-yl)methyl]-4-(4-fluorophenyl)quino- line-2-carboxamide Calc'd 409.2, Found 409.2 4-37

7-[(2,6- dimethylmorpholin- 4-yl)methyl]-4-(4- fluorophenyl)quino-line-2-carboxamide Calc'd 394.2, Found 394.2 4-38

4-(4-fluorophenyl)- 7-{[(3S)-3- methylmorpholin- 4- yl]methyl}quinoline-2-carboxamide Calc'd 380.2, Found 380.2 4-39

4-(4-fluroophenyl)- 7-{[(2S)-2- methylmorpholin- 4- yl]methyl}quinoline-2-carboxamide Calc'd 380.2, Found 380.2 4-40

4-(4-fluorophenyl)- 7-[(4- hydroxypiperidin- 1- yl)methyl]quinoline-2-carboxamide Calc'd 380.2, Found 380.2 4-41

7-[(4,4- dihydroxypiperidin- 1-yl)methyl]-4-(4- fluorophenyl)quino-line-2-carboxamide Calc'd 396.2, Found 396.2 4-42

7-[(1,1- dioxidothiomorpholin- 4-yl)methyl]-4- (4- fluorophenyl)quino-line-3-carboxamide Calc'd 414.1, Found 414.1 4-43

4-(4-fluorophenyl)- 7-[(4- methylpiperazin-1- yl)methyl]quinoline-2-carboxamide Calc'd 379.2, Found 379.2 4-44

4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl) piperidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 432.2, Found 432.2 4-45

4-(4-fluorophenyl)- 7-(piperazin-1- ylmethyl)quinoline- 2-carboxamideCalc'd 365.2, Found 365.2 4-46

4-(4-fluorophenyl)- 7-{[2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 434.1, Found 434.1 4-47

4-(4-fluorophenyl)- 7-{[4-(4-methyl- 1H-imidazol-1- yl)piperidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 444.2, Found 444.3 4-48

4-(4-fluorophenyl)- 7-{[3-(1H-1,2,4- triazol-1- yl)piperidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 431.2, Found 431.2 4-49

4-(4-fluorophenyl)- 7-{[2- (trifluoromethyl)- 5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)- yl]methyl}quinoline- 2-carboxamide Calc'd 470.2, Found470.2 4-50

7-[(4- aminopiperidin-1- yl)methyl]-4-(4- fluorophenyl)quino-line-2-carboxamide Calc'd 379.2, Found 379.2 4-51

4-(2-methyl-1,3- thiazol-5-yl)-7-{[2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 437.1, Found 437.2 4-52

4-(4-fluorophenyl)- 7-(2-oxa-8- azaspiro[4.5]dec-8- ylmethyl)quinoline-2-carboxamide Calc'd 420.2, Found 420.2 4-53

4-(1-methyl-1H- pyrazol-4-yl)-7- {[(2S)-2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 420.2, Found420.1 4-54

4-(1-methyl-1H- pyrazol-4-yl)-7- {[(2R)-2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 420.2, Found420.5 4-55

4-(2-methoxy-1,3- thiazol-5-yl)-7-{[2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 453.1, Found 453.2 4-56

7-[(2,2- dimethylmorpholin- 4-yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 380.2, Found 380.3 4-57

7-[(3,3- dimethylmorpholin- 4-yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 380.2, Found 380.3 4-58

7-{[2- (methoxymethyl) morpholin-4- yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 396.2, Found 396.3 4-59

7-{[(3S)-3- methylmorpholin- 4-yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 366.2, Found 366.2 4-60

7-{[(3R)-3- methylmorpholin- 4-yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 366.2, Found 366.2 4-61

7-{[(2R)-2- methylmorpholin- 4-yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 366.2, Found 366.2 4-62

7-{[(2S)-2- methymorpholin- 4-yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 366.2, Found 366.2 4-63

7-{[(3R,5R)-3,5- dimethymorpholin- 4-yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 380.2, Found 380.2 4-64

7-{[3-(2- methylpropyl) morph- olin-4-yl]methyl}- 4-(1-methyl-1H-pyrazol-4- yl)quinoline-2- carboxamide Calc'd 408.2, Found 408.2 4-65

4-(1-methyl-1H- pyrazol-4-yl)-7- {[(2S,6S)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd434.2, Found 434.3 4-66

4-(1-methyl-1H- pyrazol-4-yl)-7- {[(2R,6S)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd434.2, Found 434.3 4-67

4-(1H-pyrazol-4- yl)-7-{[2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 406.1, Found 406.2 4-68

7-[(4- fluoropiperidin-1- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 368.2, Found 368.2 4-69

7-[(4,4- difluoropiperidin-1- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 386.2, Found 386.2 4-70

4-(1-methyl-1H- pyrazol-4-yl)-7- {[4- (trifluoromethyl) piperidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 418.2, Found 418.2 4-71

4-(1-methyl-1H- pyrazol-4-yl)-7- {[3- (trifluoromethyl) piperidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 418.2, Found 418.2 4-72

7-[(3- fluoropiperidin-1- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 368.2, Found 368.3 4-73

7-[(3,3- difluoropiperidin-1- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 386.2, Found 386.3 4-74

4-(2-ethyl-1,3- thiazol-5-yl)-7-{[2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 451.1, Found 451.3 4-75

4-[2-(1- methylethyl)-1,3- thiazol-5-yl]-7-{[2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 465.2, Found465.3 4-76

4-(2-cyclopropyl- 1,3-thiazol-5-yl)-7- {[2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 463.1, Found463.3 4-77

4-(1-ethyl-1H- pyrazol-4-yl)-7- {[2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 434.2, Found 434.3 4-78

4-[1-(1- methylethyl)-1H- pyrazol-4-yl]-7- {[2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 448.2, Found448.3 4-79

4-[1-(2,2,2- trifluoroethyl)-1H- pyrazol-4-yl]-7- {[2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 488.2, Found488.3 4-80

4-[1- (fluoromethyl)-1H- pyrazol-4-yl]-7- {[2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 438.2, Found438.3 4-81

4-(2-methyl-1,3- oxazol-5-yl)-7-{[2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 421.1, Found 421.3 4-82

4-(1-cyclopropyl- 1H-pyrazol-4-yl)-7- {[2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 446.2, Found446.3 4-83

4-(1H-pyrazol-4- yl)-7-{[(2R)-2- (trifluoromethyl) morpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 406.1, Found 406.3 4-84

4-[1- (difluoromethyl)- 1H-pyrazol-4-yl]-7- {[2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 456.1, Found456.3 4-85

4-[1- (fluoromethyl)-1H- pyrazol-4-yl]-7- {[(2)S-2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 438.2, Found438.3 4-86

4-[1- (fluoromethyl)-1H- pyrazol-4-yl]-7- {[(2R)-2- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 438.2, Found438.3 4-87

4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 433.2, Found 433.3 4-88

4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 433.2, Found 433.3 4-89

4-(4-fluorophenyl)- 7-{[2- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 433.2, Found 433.3 4-90

4-(1-methyl-1H- pyrazol-4-yl)-7- {[(2R,5R)-5- methyl-2-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd434.2, Found 434.3 4-91

4-(1-methyl-1H- pyrazol-4-yl)-7- {[(2R,5S)-5- methyl-2-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd434.2, Found 434.2 4-92

4-(1-methyl-1H- pyrazol-4-yl)-7- {[(2S,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd434.2, Found 434.3 4-93

7-{[4-ethyl-3- (trifluoromethyl) piperazin-1- yl]methyl}-4-(4-fluorophenyl)quino- line-2-carboxamide Calc'd 461.2, Found 461.3 4-94

4-(4-fluorophenyl)- 7-{[4-methyl-3- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 447.2, Found 447.3 4-95

7-{[(6R)-2,2- dimethyl-6- (trifluoromethyl) morpholin-4-yl]methyl}-4-(1- methyl-1H-pyrazol- 4-yl)quinoline-2- carboxamide Calc'd448.2, Found 448.3 4-96

7-{[(2R)-5,5- dimethyl-2- (trifluoromethyl) morpholin-4-yl]methyl}-4-(1- methyl-1H-pyrazol- 4-yl)quinoline-2- carboxamide Calc'd448.2, Found 448.3 4-97

7-{[(2R,6R)-2- methyl-6- (trifluoromethyl) morpholin-4-yl]methyl}-4-(1H- pyrazol-4- yl)quinoline-2- carboxamide Calc'd 420.2,Found 420.2 4-98

4-(1-methyl-1H- pyrazol-4-yl)-7- {[2-(2,2,2- trifluoroethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 434.2, Found434.3 4-99

7-[(2- ethylmorpholin-4- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 380.2, Found 380.3 4-100

7-{[2-(2- methylpropyl)morph- olin-4-yl]methyl}- 4-(1-methyl-1H-pyrazol-4- yl)quinoline-2- carboxamide Calc'd 408.2, Found 408.3 4-101

4-(4-fluorophenyl)- 7-{[(2R)-2-methyl- 5- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 447.2, Found 447.3 4-102

4-(4-fluorophenyl)- 7-{[(2R)-2-methyl- 5- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 447.2, Found 447.3 4-103

4-(4-fluorophenyl)- 7-{[(3R)-3- methylpiperazin-1- yl]methyl}quinoline-2-carboxamide Calc'd 379.2, Found 379.3 4-104

4-(4-fluorophenyl)- 7-{[(3S)-3- methylpiperazin-1- yl]methyl}quinoline-2-carboxamide Calc'd 379.2, Found 379.3 4-105

4-(4-fluorophenyl)- 7-[(8aR)- hexahydropyrrolo [1,2-a]pyrazin-2(1H)-ylmethyl]quinoline- 2-carboxamide Calc'd 405.2, Found 405.3 4-106

7-{[3- (difluoromethyl) piperazin-1- yl]methyl}-4-(4-fluorophenyl)quino- line-2-carboxamide Calc'd 415.2, Found 415.2 4-107

7-{[3- (difluoromethyl) piperazin-1- yl]methyl}-4-(4-fluorophenyl)quino- line-2-carboxamide Calc'd 415.2, Found 415.2 4-108

7-[(3-tert- butylpiperazin-1- yl)methyl]-4-(4- fluorophenyl)quino-line-2-carboxamide Calc'd 421.2, Found 421.3 4-109

4-(4-fluorophenyl)- 7-{[3-(1- methylethyl)pipera- zin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 407.2, Found 407.3 4-110

7-[(3- cyclopropylpiperazin- 1-yl)methyl]-4- (4- fluorophenyl)quino-line-2-carboxamide Calc'd 405.2, Found 405.3 4-111

7-{[3- (fluoromethyl)piper- azin-1-yl]methyl}- 4-(4- fluorophenyl)quino-line-2-carboxamide Calc'd 397.2, Found 397.3 4-112

4-(4-fluorophenyl)- 7-{[3-methyl-5- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 447.2, Found 447.3 4-113

4-(4-fluorophenyl)- 7-{[3-methyl-5- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 447.2, Found 447.3 4-114

4-(4-fluorophenyl)- 7-{[3-methyl-5- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 447.2, Found 447.3 4-115

4-(4-fluorophenyl)- 7-{[3-methyl-5- (trifluoromethyl) piperazin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 447.2, Found 447.3 4-116

4-[2- (fluoromethyl)-1,3- thiazol-5-yl]-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd469.1, Found 469.2 4-117

4-[2- (difluoromethyl)- 1,3-thiazol-5-yl]-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd487.1, Found 487.2 4-118

4-[1- (difluoromethyl)- 1H-pyrazol-4-yl]-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd470.2, Found 470.2 4-119

4-(1-methyl-1H- pyrazol-4-yl)-7- {[2- (trifluoromethyl) thiomorpholin-4-yl]methyl}quinoline- 2-carboxamide Calc'd 436.1, Found 436.2 4-120

7-(5- azaspiro[2.5]oct-5- ylmethyl)-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 376.2, Found 376.3 4-121

7-{[(3R)-3- hydroxypiperidin- 1-yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 366.2, Found 366.3 4-122

7-{[(3S)-3- hydroxypiperidin- 1-yl]methyl}-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 366.2, Found 366.3 4-123

4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl) piperidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 432.2, Found 432.3 4-124

4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl) piperidin-1-yl]methyl}quinoline- 2-carboxamide Calc'd 432.2, Found 432.3 4-125

4-(5-methyl-1,3- thiazol-2-yl)-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd451.1, Found 451.2 4-126

4-(3- methylisothiazol-5- yl)-7-{[(2R,6R)-2- methyl-6- (trifluoromethyl)morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd 451.1, Found451.2 4-127

7-[(2-cyclopropyl- 1,1- dioxidothiomorpholin- 4-yl)methyl]-4-(1-methyl-1H- pyrazol-4- yl)quinoline-2- carboxamide Calc'd 440.2, Found440.3 4-128

4-(2-amino-1,3- thiazol-5-yl)-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd452.1, Found 452.2 4-129

4-(3-methyl-1,2,4- thiadiazol-5-yl)-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd452.1, Found 452.2 4-130

7-(6- azaspiro[2.5]oct-6- ylmethyl)-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 376.2, Found 376.3 4-131

7-{[2- (fluoromethyl)piper- idin-1-yl]methyl}- 4-(1-methyl-1H-pyrazol-4- yl)quinoline-2- carboxamide Calc'd 382.2, Found 382.3 4-132

7-(4- azaspiro[2.5]oct-4- ylmethyl)-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 376.2, Found 376.3 4-133

4-(1,5-dimethyl- 1H-pyrazol-4-yl)-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd448.5, Found 448.4 4-134

7-{[(2R,6R)-2- methyl-6- (trifluoromethyl) morpholin-4- yl]methyl}-4-(1,3,5-trimethyl- 1H-pyrazol-4- yl)quinoline-2- carboxamide Calc'd462.5, Found 462.4 4-135

4-(1,3-dimethyl- 1H-pyrazol-4-yl)-7- {[(2R,6R)-2- methyl-6-(trifluoromethyl) morpholin-4- yl]methyl}quinoline- 2-carboxamide Calc'd448.5, Found 448.4

Example 5 Synthesis of4-(4-fluorophenyl)-7-(pyrrolidin-1-ylcarbonyl)quinoline-2-carboxamide(5-4) 7-(Dibromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (5-1)

4-(4-Fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6, 7.86 g, 30.0mmol, 1.0 equiv.) was dissolved in carbon tetrachloride (150.0 mL, 0.2M). NBS (5.44 g, 30.6 mmol, 1.02 equiv) and AIBN (148.0 mg, 0.899 mmol,0.03 equiv.) were added and the mixture was heated to reflux for 5hours. The mixture was cooled to room temperature and the whiteprecipitate was filtered off. The filtrate was concentrated and theresidue was purified by column chromatography on a silica gel column,eluting with EtOAc/Isohexane (0-50%) to afford7-(dibromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (5-1, 1.27g, 10.1%). LRMS m/z (M+H)⁺ 421.1 found, 421.1 required.

4-(4-Fluorophenyl)-7-formylquinoline-2-carboxamide (5-2)

To a solution of7-(dibromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (5-1, 1.27g, 3.02 mmol, 1.0 equiv.) in 1, 4-dioxane (40.0 mL, 0.075 M) was added aslurry of silver nitrate (2.05 g, 12.1 mmol, 4.0 equiv.) in water (20.0mL). The resulting mixture was heated to reflux for 24 hours, thencooled, and filtered through a pad of celite. The filtrate was washedwith ethyl acetate, the layers were separated and the organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated to give4-(4-fluorophenyl)-7-formylquinoline-2-carboxamide (5-2, 850.0 mg,96.0%) as a white solid. LRMS m/z (M+H)⁺ 295.1 found, 295.1 required.

2-(Aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3)

To a solution of 4-(4-fluorophenyl)-7-formylquinoline-2-carboxamide(5-2, 200.0 mg, 0.680 mmol, 1.0 equiv.) and 2-methyl-2-butene (3.96 mL,37.4 mmol, 55 equiv.) in t-BuOH (14.0 mL, 0.05 M) was added a solutionof sodium chlorite (553.0 mg, 6.12 mmol, 9 equiv.) and sodium dihydrogenphosphate monohydrate (559.0 mg, 4.08 mmol, 6 equiv.) in water (6.5 mL).The resulting mixture was stirred at room temperature for 1 hour. Awhite solid precipitated. Water (100.0 ml) was added and the mixturestirred for 30 minutes. The solid was collected via suction filtration,washed with water, dried in vacuo to give2-(aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3,150.0 mg, 71.1%) as a white solid. LRMS m/z (M+H)⁺ 311.1 found, 311.1required.

4-(4-Fluorophenyl)-7-(pyrrolidin-1-ylcarbonyl)quinoline-2-carboxamide(5-4)

2-(Aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3,50.0 mg, 0.161 mmol, 1.0 equiv), pyrrolidine (11.5 mg, 0.161 mmol, 1.0equiv.), BOP (93.0 mg, 0.209 mmol, 1.3 equiv.), and TEA (0.0670 mL,0.483 mmol, 3 equiv) were dissolved into DMF (1.0 mL) and stirred atroom temperature for 1 hour. The mixture was diluted with methylenechloride, washed with water, brine, dried over MgSO₄, filtered andconcentrated. The crude residue was purified by reverse phase HPLC(H₂O/CH₃CN gradient w/ 0.1% TFA modifier) to afford4-(4-Fluorophenyl)-7-(pyrrolidin-1-ylcarbonyl)quinoline-2-carboxamide(5-4, 50.0 mg, 85.0%) as a colorless solid. ¹H NMR (500 MHz, CDCl₃): δ8.324 (d, J=1.47 Hz, 1H); 8.273 (s, 1H); 8.251 (br s, 1H); 8.026 (d, J8.78 Hz, 1H); 7.762 (dd, J₁=8.54 Hz, J₂=1.71 Hz, 1H); 7.501-7.529 (m,2H); 7.246-7.286 (m, 2H); 6.750 (br s, 1H); 3.765 (tr, J=6.95 Hz, 2H);3.567 (tr, J=6.68 Hz, 2H); 2.055 (quint, J=6.78 Hz, 2H); 1.962 (quint,J=6.65 Hz, 2H). LRMS m/z (M+H)⁺ 364.1 found, 364.1 required.

The following compounds have been prepared according to proceduressimilar to those found in Scheme 5 selecting the appropriate quinolinederivative and boronic acid derivatives and provide examples ofcompounds in the invention.

TABLE 5 Exact Mass Example Structure IUPAC Name [M + H]⁺ 5-5

4-(4-fluorophenyl)-7- (piperidin-1- ylcarbonyl)quinoline-2- carboxamideCalc'd 378.2, Found 378.2 5-6

4-(4-fluorophenyl)-7- (morpholin-4- ylcarbonyl)quinoline-2- carboxamideCalc'd 380.1, Found 380.3

Example 6.1 Synthesis of7-((2-cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide(6-2)7-((2-Cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile(6-1)

After degassing with N₂, a mixture of7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 650 mg, 2.31mmol),2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(580 mg, 2.36 mmol), Pd(dppf)Cl₂—CH₂Cl₂ adduct (94 mg, 0.11 mmol), andK₃PO₄ (1960 mg, 9.24 mmol) in 1,4-dioxane (13.7 mL) and H₂O (1.7 mL) washeated at 100° C. for 30 min under microwave condition. The mixture wascooled to room temperature, and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(528 mg, 2.54 mmol) was added. After degassing with N₂, the mixture wasthen heated at 115° C. for 30 min under microwave condition. Thereaction mixture was cooled, diluted with H₂O (10 mL) and the mixturewas extracted with ethyl acetate (2×50 mL). The combined organicfractions were washed with brine, dried (Na₂SO₄), filtered and thesolvent was evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel, eluting withEtOAc/Hexane (0-100%) to afford7-((2-cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile(6-1, 649 mg, 77%). LRMS (M+H)⁺ 367.3 found, 367.2 required.

7-((2-Cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide(6-2)

7-(2-Cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile(5-1, 71.3 mg, 0.19 mmol.) was dissolved in acetone (6.5 mL) and sodiumpercarbonate (85 mg, 0.58 mmol.) in H₂O (3.24 mL) was added slowly. Theresulting mixture was stirred at room temperature for one hour.Saturated NH₄Cl (1.5 mL) was added, followed by H₂O (30 mL) to give awhite precipitation. The solid was collected by filtration, washed withH₂O and then Hexane, and dried under vacuum to provide7-((2-cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide(6-2, 72.1 mg, 96.0%) as a white solid. LRMS m/z (M+H)⁺ 385.3 found,385.2 required.

Example 6.2 Synthesis of4-(4-fluorophenyl)-7-(pyrimidin-5-ylmethyl)quinoline-2-carboxamide (6-3)4-(4-Fluorophenyl)-7-(pyrimidin-5-ylmethyl)quinoline-2-carboxamide (6-3)

Degassed DME (1237 μl)/Water (619 up was added to7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 100 mg,0.278 mmol), pyrimidin-5-ylboronic acid (41.4 mg, 0.334 mmol), Pd(PPh₃)₄(16.09 mg, 0.014 mmol), and Na₂CO₃ (62.0 mg, 0.585 mmol). The reactionwas heated at 100° C. in the microwave for 10 minutes. The reaction wasquenched with water and the mixture was extracted with ethyl acetate(×3). The combined organic fractions were dried (MgSO₄), filtered andthe solvent was evaporated under reduced pressure. The crude materialwas purified by flash column chromatography (12 g SiO₂, 0-100%EtOAc/hexanes) to afford impure product. The material was purifiedfurther by reverse phase HPLC (20×150 mm, Waters Sunfire, Solvent A=0.1%TFA/H₂O, Solvent B=0.1% TFA/MeCN, 20 ml/min) to afford, after basicworkup,4-(4-fluorophenyl)-7-(pyrimidin-5-ylmethyl)quinoline-2-carboxamide (6-3,8.16 mg, 8.18% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 9.14(s, 1H); 8.68 (s, 2H); 8.23 (s, 1H); 8.05 (s, 1H); 7.97 (s, 1H); 7.93(d, J=8.7 Hz, 1H); 7.50 (dd, J=8.5, 5.4 Hz, 2H); 7.42 (dd, J=8.7, 1.8Hz, 1H); 7.24 (t, J=8.5 Hz, 2H); 5.64 (s, 1H); 4.22 (s, 2H). LRMS m/z(M+H)⁺ 359.2 found, 359.4 required.

The following compounds have been prepared according to proceduressimilar to those found in Scheme 6.1 and 6.2 selecting the appropriatequinoline derivative and boronic acid derivatives and provide examplesof compounds in the invention.

TABLE 6 IUPAC Exact Mass Example Structure Name [M + H]+ 6-4 

4-(1-methyl- 1H-pyrazol-4- yl)-7-{[2- (trifluoromethyl) pyridin-4-yl]methyl} quinoline-2- carbonitrile Calc'd 394.1, Found 394.1 6-5 

4-(4- fluorophenyl)- 7-(pyridin-3- ylmethyl) quinoline-2- carboxamideCalc'd 358.1, Found 358.2 6-6 

7-[(6- cyanopyridin- 3-yl)methyl]- 4-(4- fluorophenyl) quinoline-2-carboxamide Calc'd 383.1, Found 383.1 6-7 

4-(4- fluorophenyl)- 7-{[2- (hydroxymethyl) pyridin-4-yl] methyl}quinoline-2- carboxamide Calc'd 388.1, Found 388.1 6-8 

7-[(3-chloro-2- methoxypyridin- 4-yl)methyl]-4- (4-fluorophenyl)quinoline-2- carboxamide Calc'd 422.1, Found 422.1 6-9 

4-(4-fluorophenyl)- 7-[(2-methoxy- pyrimidin-5-yl) methyl] quinoline-2-carboxamide Calc'd 389.1, Found 389.1 6-10

4-(4-fluorophenyl)- 7-[(4-methylpyridin- 3-yl)methyl] quinoline-2-carboxamide Calc'd 372.2, Found 372.1 6-11

4-(4-fluorophenyl)- 7-[(2-methoxy- pyrimidin- 5-yl)methyl] quinoline-2-carboxamide Calc'd 389.1, Found 389.1 6-12

4-(4-fluorophenyl)- 7-[(5-methoxy- pyridin-3-yl) methyl] quinoline-2-carboxamide Calc'd 388.1, Found 388.1 6-13

4-(4-fluorophenyl)- 7-(4-methoxybenzyl) quinoline- 2-carboxamide Calc'd387.2, Found 387.1 6-14

4-(4-fluorophenyl)-7- [(2-methoxypyridin- 4-yl)methyl] quinoline-2-carboxamide Calc'd 388.1, Found 388.1 6-15

7-[(2- chloropyrimidin- 5-yl)methyl]-4- (1-methyl- 1H-pyrazol-4-yl)quinoline- 2-carboxamide Calc'd 379.1, Found 379.1 6-16

7-[(2- fluoropyrimidin-5- yl)methyl]-4- (1-methyl- 1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 363.1, Found 363.1 6-17

7-[(6- methoxypyridin-3- yl)methyl]-4- (1-methyl- 1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 374.2, Found 374.2 6-18

7-[4-fluoro-3- (trifluoromethyl) benzyl]-4- (1-methyl- 1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 429.1, Found 429.1 6-19

7-[(2- methoxypyrimidin- 5-yl)methyl]-4- (1-methyl- 1H-pyrazol-4-yl)quinoline- 2-carboxamide Calc'd 375.2, Found 375.1 6-20

7-[(2- cyanopyridin- 4-yl)methyl]- 4-(1-methyl- 1H-pyrazol-4-yl)quinoline- 2-carboxamide Calc'd 369.1, Found 369.1 6-21

4-(1-methyl-1H- pyrazol-4-yl)-7-{[2- (trifluoromethyl)pyridin-4-yl]methyl} quinoline-2- carboxamide Calc'd 412.1, Found 412.36-22

4-(1-methyl- 1H-pyrazol-4- yl)-7-{[2- (trifluoromethyl) pyridin-3-yl]methyl} quinoline-2- carboxamide Calc'd 412.1, Found 412.1 6-23

4-(1-methyl- 1H-pyrazol-4- yl)-7-{[6- (trifluoromethyl) pyridin-2-yl]methyl} quinoline-2- carboxamide Calc'd 412.1, Found 412.1 6-24

7-[(2,6- dimethylpyridin- 4-yl)methyl]-4- (1-methyl- 1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 372.2, Found 372.3 6-25

7-{[2-chloro-6- (trifluoromethyl) pyridin-4- yl]methyl}-4- (1-methyl-1H-pyrazol-4- yl)quinoline-2- carboxamide Calc'd 446.1, Found 446.2 6-26

7-{[2-cyclopropyl- 6-(trifluoromethyl) pyridin-4-yl] methyl}-4-(1-methyl- 1H-pyrazol-4-yl) quinoline- 2-carboxamide Calc'd 452.2, Found452.3

Example 7.1 Synthesis of8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide (7-5) Dimethyl(2E)-2-[(2-fluorophenyl)amino]but-2-enedioate (7-1)

To a solution 2-fluoroaniline (1.00 g, 9.00 mmol) in MeOH (11.1 mL) at0° C. was added dimethyl acetylenedicarboxylate (DMAD, 1.34 mL, 10.8mmol). The reaction was stirred at room temperature for 2 h. The mixturewas concentrated and the residue was purified by silica gel flashchromatography (gradient 0-25% EtOAc in Hexanes) to give dimethyl(2E)-2-[(2-fluorophenyl)amino]but-2-enedioate (7-1, 1.9 g, 83%). LRMSm/z (M+H)⁺ 254.4 found, 254.4 required.

8-Fluoro-4-hydroxyquinoline-2-carboxylate (7-2)

Dimethyl (2E)-2-[(2-fluorophenyl)amino]but-2-enedioate (7-1, 1.90 g,7.50 mmol) was dissolved in Eaton's reagent (8.00 mL, 50.4 mmol) andheated at 55° C. for 1 h. The LC-MS showed clean conversion. Thereaction mixture was cooled to room temperature and slowly poured into acold saturated solution of NaHCO₃. The light-yellow precipitate formedwas collected by filtration, washed with H₂O and dried in vacuum toprovide methyl 8-fluoro-4-hydroxyquinoline-2-carboxylate (7-2). LRMS m/z(M+H)⁺ 222.4 found, 222.4 required.

Methyl 4-bromo-8-fluoroquinoline-2-carboxylate (7-3)

To a solution of 8-fluoro-4-hydroxyquinoline-2-carboxylate (7-2, 0.860g, 3.89 mmol) in a mixture of acetonitrile (0.884 mL) and toluene (8.84ml) was added phosphorus oxybromide (1.23 g, 4.28 mmol). The reactionmixture was heated at 75° C. for 0.5 h. A second portion of phosphorusoxybromide (0.50 g) was added and heated at 75° C. for another 30 min.The LC-MS showed completed reaction. The reaction was cooled andcarefully quenched with ice-water. The mixture was extracted with CH₂Cl₂and EtOAc consecutively. The combined organic layers were dried andconcentrated. The residue was purified by silica gel flashchromatography (gradient 0-25% EtOAc in hexanes) to give methyl4-bromo-8-fluoroquinoline-2-carboxylate (7-3). LRMS m/z (M+H)⁺ 284.3found, 284.3 required.

8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid (7-4) Methyl4-bromo-8-fluoroquinoline-2-carboxylate (7-3, 100.0 mg, 0.352 mmol),4-Fluorophenylboronic acid (59.1 g, 0.422 mmol), Tetrakis (20.3 mg,0.0180 mmol), and Na₂CO₃ (0.704 ml, 0.704 mmol) were added into1,4-Dioxane (1.0 mL) in a microwave reaction vessel. The mixture wasirradiated with microwave at 100° C. for 30 min. Cooled to roomtemperature, aqueous Sodium Hydrogen Carbonate (saturate, 2.0 mL) wasadded and extracted with Ethyl Acetate (2×10.0 mL). The combined organicfractions were washed with brine, dried over MgSO₄, filtered and thesolvent was evaporated under reduced pressure to give8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid (7-4, 100.0 mg,100.0% crude). LRMS m/z (M+H)⁺ 286.2 found, 2862 required.

8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide (7-5)

8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid (7-4, 100.0 mg,0.351 mmol), ammonium formate (88.0 mg, 1.40 mmol), BOP (202.0 mg, 0.456mmol), and triethylamine (0.147 ml, 1.052 mmol) were dissolved into DMF(1.0 mL), and the resulting mixture was stirred at 60° C. for 5 hours.The mixture was cooled and diluted with Methylene Chloride, washed withwater, brine, dried over MgSO₄, filtered and concentrated. The cruderesidue was purified by reverse phase HPLC (H₂O/ CH₃CN gradient w/ 0.1%TFA modifier) to afford8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide (7-5, 9.00 mg, 9.0%)as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ 8.209 (s, 1H); 8.138(br s, 1H); 8.658 (d, J=8.62 Hz, 1H); 7.379-7.493 (m, 4H); 7.145-7.214(m, 2H); 6.004 (br s, 1H). LRMS m/z (M+H) 285.1 found, 285.1 required.

Example 7.2 Synthesis of7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide(7-13) Dimethyl (2E)-2-[(2-fluoro-3-methylphenyl)imino]butanedioate(7-6)

3-Amino-2-fluorotoluene (4.89 g, 39.1 mmol), dimethyl 2-oxobutanedioate(6.26 g, 39.1 mmol), and TosicAcid (0.223 g, 1.172 mmol) were heated atreflux under Dean-Stark conditions for 1 hour. The solvent was removedin vacuo and the residue purified by column chromatography on a silicagel column, eluting with EtOAc/hexane (0-15%) to afford Dimethyl(2E)-2-[(2-fluoro-3-methylphenyl)imino]butanedioate (7-6, 5.48 g, 53%yield) as a clear oil, LCMS shows the compound is 100% pure, LRMS m/z(M+H)⁺ 268.2 found, 268.1 required.

Methyl 8-fluoro-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (7-7)

Dimethyl (2E)-2-[(2-fluoro-3-methylphenyl)imino]butanedioate (7-6, 3.27g, 12.24 mmol) in DMA (24.47 ml) was heated at 240° C. in the microwavefor 5 min. The solvent was evaporated under reduced pressure and theresidue triturated with ether to afford a tan solid. The desired productwas filtered off and washed with ether till the ether ran colorlessaffording Methyl8-fluoro-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (7-7, 1.23 g,43% yield) as a tan solid, LCMS shows 93% pure, LRMS m/z (M+H)⁺ 236.1found, 236.1 required.

Methyl 4-chloro-8-fluoro-7-methylquinoline-2-carboxylate (7-8)

Methyl 8-fluoro-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (7-7,1.23 g, 5.23 mmol) in POCl₃ (11 ml) was heated at 100° C. for 1 hour.The excess POCl₃ was removed in vacuo. The resulting residue wastriturated with ether, then filtered and washed with ether till no browncolor remained in the ether. The remaining solid was Methyl4-chloro-8-fluoro-7-methylquinoline-2-carboxylate (7-8, 993 mg, 75%yield) 100% pure by LCMS, LRMS m/z (M+H)⁺ 254.0 found, 254.1 required.

Methyl 8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate (7-9)

Methyl 4-chloro-8-fluoro-7-methylquinoline-2-carboxylate (7-8, 993 mg,3.91 mmol), (4-Fluorophenyl)boronic acid (575 mg, 4.11 mmol), andPd(Ph₃P)₄ (226 mg, 0.196 mmol) were dissolved in degassed toluene (25mL). Degasses EtOH (2.7 mL) was added followed by degassed 2M aq. SodiumCarbonate (4.31 mL, 8.61 mmol). The reaction was heated at 75° C.overnight then quenched with water and the mixture was extracted withethyl acetate (×3). The combined organic fractions were dried (MgSO₄),filtered and the solvent was evaporated under reduced pressure. Theresidue was triturated with ether to afford Methyl8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate (7-9, 991mg, 81% yield) as a tan solid, LCMS shows the compound is 89% pure, LRMSm/z (M+H)⁺ 314.1 found, 314.0 required.

Methyl7-(bromomethyl)-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate(7-10)

Methyl 8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate 7-9(991 mg, 3.16 mmol), Benzoyl peroxide (102 mg, 0.316 mmol), and NBS (591mg, 3.32 mmol) were heated at reflux in CCl₄ for 5 hours. The solventwas removed in vacuo and the residue purified by column chromatographyon a silica gel column, eluting with EtOAc/hexane (0-50%) to affordMethyl7-(bromomethyl)-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-10(1.05 g, 85% yield) as a white solid, LCMS shows the compound is 67%pure, LRMS m/z (M+H)⁺ 392.0 found, 392.1 required.

Methyl7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate(7-11)

Cs₂CO₃ (1.745 g, 5.35 mmol) was added to a solution of Succinimide(0.292 g, 2.94 mmol) and methyl7-(bromomethyl)-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-10(1.05 g, 2.68 mmol) in DMF (13.39 ml) and the reactant stirred at it for30 min. The reaction was quenched with KH₂PO₄ (saturated) and themixture was extracted with ethyl acetate (×3). The combined organicfractions were dried (MgSO₄), filtered and the solvent was evaporatedunder reduced pressure. The solvent was removed in vacuo and the residuepurified by column chromatography on a silica gel column, eluting withEtOAc/hexane (0-100%) to afford Methyl7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate7-11 as a white solid, LCMS shows the compound is 90% pure, LRMS m/z(M+H)⁺ 411.2 found, 411.1 required.

7-[(2,5-Dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylicacid (7-12)

6M HCl (2964 μl) was added to a solution of methyl7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate7-11 (629 mg, 1.482 mmol) in Acetic Acid (2964 μl) and the reactionheated at 120° C. for 10 min in the microwave. The reaction was quenchedwith KH₂PO₄ (saturated) and the mixture was extracted with ethyl acetate(×3). The combined organic fractions were dried (MgSO₄), filtered andthe solvent was evaporated under reduced pressure to afford7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylicacid 7-12 (499 mg, 85% yield) as a white solid, 100% pure by LCMS, LRMSm/z (M+H)⁺ 397.2 found, 397.1 required.

7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide(7-13)

TEA (105 μl, 0.757 mmol) was added to a solution of7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylicacid 7-12 (100 mg, 0.252 mmol) and HATU (96 mg, 0.252 mmol) in DMF (1262μl). Ammonium Hydroxide (50.5 μl, 0.757 mmol) was added and the reactionstirred for 15 min at rt. The reaction was quenched with aqueous sodiumhydrogen carbonate (saturated) and the mixture was extracted with ethylacetate (×3). The combined organic fractions were dried (MgSO₄),filtered and the solvent was evaporated under reduced pressure. Theresidue was purified by column chromatography on a silica gel column,eluting with EtOAc/hexane (0-100%) to afford7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide7-13 (63 mg, 63% yield) as a white solid, LCMS shows the compound is100% pure ¹H NMR (500 MHz, CDCl₃): δ 8.28 (1H, s), 8.14 (1H, s), 7.68(1H, d, J=8.85 Hz), 7.54 (1H, dd, J=8.86, 6.65 Hz), 7.50-7.46 (2H, m),7.25-7.20 (2H, m), 5.69 (1H, s), 4.99 (2H, s), 2.78 (4H, s). LRMS m/z(M+H)⁺ 396.2 found, 396.1 required.

Example 7.3 Synthesis of (R)- and(S)-(S)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(7-20a and 7-20b) (E)-dimethyl 2-(2-fluoro-3-methylphenylimino)succinate(7-14)

At 0° C., dimethyl acetylenedicarboxylate (8.70 mL, 70.4 mmol) was addeddropwise to a solution 2-fluoro-3-methylaniline (7.34 g, 58.7 mmol) inMeOH (58.7 mL). After stirring at room temperature overnight, thereaction mixture was concentrated to dryness. The residue was purifiedby silica gel flash chromatography (gradient 0-60% EtOAc/Hexanes) togive (E)-dimethyl 2-(2-fluoro-3-methylphenylimino)succinate (7-14, 14.59g, 93%). LRMS m/z (M+H)⁺ 268.3 found, 268.1 required.

Methyl 8-fluoro-4-hydroxy-7-methylquinoline-2-carboxylate (7-15)

A mixture of (E)-dimethyl 2-(2-fluoro-3-methylphenylimino)succinate(7-14, 14.59 g, 54.6 mmol) and Eaton's reagent (52.0 mL, 328 mmol) washeated at 50° C. for 1 h. After cooling to room temperature, the mixturewas added slowly to a cold sat. NaHCO₃ solution (gas released!),followed by EtOAc extraction (twice). The combined organic fractionswere washed with brine, dried (Na₂SO₄), filtered and the solvent wasevaporated under reduced pressure to afford methyl8-fluoro-4-hydroxy-7-methylquinoline-2-carboxylate (7-15, 11.9 g). LRMSm/z (M±H)⁺ 236.2 found, 236.1 required.

Methyl 4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16)

A mixture of (methyl 8-fluoro-4-hydroxy-7-methylquinoline-2-carboxylate(7-15, 842.1 mg, 3.58 mmol) and POBr₃ (1129 mg, 3.94 mmol) in Toluene(8.14 mL) and CH₃CN (0.81 mL) was heated at 75° C. for 1 h. Aftercooling to room temperature, the mixture was poured to a mixture ofice-H₂O, followed by CH₂Cl₂ extraction (twice). The combined organicfractions were dried (Na₂SO₄), filtered and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel flashchromatography (gradient 0-50% EtOAc/Hexanes) to afford methyl4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 710 mg). LRMS(M+H)⁺298.1 found, 298.0 required.

Methyl8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate(7-17)

After degassing with N₂, a mixture of methyl4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 650 mg, 2.18mmol.),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(544 mg, 2.62 mmol) Pd(dppf)Cl₂—CH₂Cl₂ adduct (89 mg, 0.11 mmol), andK₃PO₄ (1388 mg, 6.54 mmol) in 1,4-dioxane (12.9 mL) and H₂O (1.6 mL) washeated at 100° C. for 20 min under microwave condition. After cooling toroom temperature, the reaction mixture was filtered and concentrated.The residue was purified by column chromatography on silica gel, elutingwith EtOAc/Hexane (0-100%) to afford methyl8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate(7-17, 481 mg, 74%). LRMS m/z (M+H)⁺ 300.3 found, 300.1 require.

Methyl7-(bromomethyl)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate(7-18)

After degassing with N₂, a mixture of methyl8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate(7-17, 169.2 mg, 0.57 mmol), NBS (106 mg, 0.59 mmol) and benzoylperoxide (13.7 mg, 0.057 mmol) in CCl₄ (2.8 ml) was stirred at 80° C.After 5 h, the solvent was removed and the residue was partitionedbetween EtOAC and sat. NaHCO₃. The organic layer was washed with water,dried over Na₂SO₄ and filtered. Concentration afforded the crude methyl7-(bromomethyl)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate,which was used without further purification (7-18). LRMS m/z (M+H)⁺378.2 found, 378.0 required.

(R)-Methyl8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxylate(7-19a) and (S)-Methyl8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxylate(7-19b)

Cs₂CO₃ (345 mg, 1.06 mmol) was added to a mixture of methyl7-(bromomethyl)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate(7-18, 160 mg, 0.42 mmol) and 2-(trifluoromethyl)morpholine (79 mg, 0.51mmol) in DMF (4.2 mL). After stirring at room temperature for 2 h, themixture was diluted with EtOAc, washed with H₂O, then brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel, eluting withEtOAc/Hexane (0-100%) to afford methyl8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate asracemic mixture (31.4 mg, 16%). LRMS m/z (M+H)⁺ 453.3 found, 453.1required. Chiral separation using SFC chromatography provided (R)-methyl8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxylate(7-19a, 15 mg) and (S)-methyl8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxylate(7-19b, 14.3 mg).

(R)-8-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(7-20a)

A mixture of(R)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(7-19a, 15.3 mg) in 7 N NH₃ in MeOH (372 uL) was stirred at roomtemperature for 2 h. Concentration and washing with the solid withhexane provided(R)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(7-20a, 12.8 mg) as white solid. LRMS m/z (M+H)⁺ 438.3 found, 438.3required.

(S)-8-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(7-20b)

By applying the same synthetic procedure for 7-20a, from(S)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(7-19b, 14 mg),(S)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxamide(7-20b, 13 mg) was prepared as white solid. LRMS m/z (M+H)⁺ 438.3 found,438.3 required.

The following compounds have been prepared according to proceduressimilar to those found in Scheme 7.1, 7.2, and 7.3 selecting theappropriate aniline derivative, boronic acid derivatives, andnucleophile and provide examples of compounds in the invention.

TABLE 7 IUPAC Exact Mass Example Structure Name [M + H]⁺ 7-21

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-6-fluoro-4- (4-fluorophenyl)quinoline- 2-carboxamide Calc'd 396.1, Found 396.1 7-22

7-[(2,5- dioxopyrrolidin-1- yl)methyl]-5-fluoro-4- (4-fluorophenyl)quinoline- 2-carboxamide Calc'd 396.1, Found 396.1 7-23

8-fluoro-4-(4- fluorophenyl)-7-[(2- methoxypyrimidin-5-yl)methyl]quinoline-2- carboxamide Calc'd 407.1, Found 407.1 7-24

8-fluoro-4-(4- fluorophenyl)-7-({4- [1-hydroxy-1-(trifluoromethyl)propyl]- 1H-imidazol-1-yl} methyl)quinoline-2-carboxamide Calc'd 491.2, Found 491.2 7-25

7-[(2- cyclopropylpyrimidin- 5-yl)methyl]-8-fluoro- 4-(4-fluorophenyl)quinoline- 2-carboxamide Calc'd 417.2, Found 417.1 7-26

8-fluoro-4-(4- fluorophenyl)-7-{[6- (hydroxymethyl) pyridin-3-yl]methyl}quinoline-2- carboxamide Calc'd 406.1, Found 406.1 7-27

8-fluoro-7-[(4- fluoropiperidin-1- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 386.2, Found 386.3 7-28

8-fluoro-4-(3-fluoro-4- methoxyphenyl)-7-({4- [1-hydroxy-1-(trifluoromethyl)propyl]- 1H-imidazol-1-yl} methyl)quinoline-2-carboxamide Calc'd 521.2, Found 521.2 7-29

8-fluoro-4-(2-fluoro-4- methoxyphenyl)-7-({4- [1-hydroxy-1-(trifluoromethyl)propyl]- 1H-imidazol-1- yl}methyl)quinoline-2-carboxamide Calc'd 521.2, Found 521.2 7-30

8-fluoro-7-[(2- methoxypyridin-3- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 392.2, Found 392.1 7-31

8-fluoro-4-(1-methyl- 1H-pyrazol-4-yl)-7-{[6- (trifluoromethyl)pyridin-3-yl]methyl}quinoline-2- carboxamide Calc'd 430.1, Found 430.1 7-32

7-[(4,4-dimethyl-2,5- dioxoimidazolidin-1- yl)methyl]-8-fluoro-4-(1-methyl-1H-pyrazol- 4-yl)quinoline-2- carboxamide Calc'd 411.2, Found411.1 7-33

7-[(2- cyclopropylpyrimidin- 5-yl)methyl]-8-fluoro- 4-(1-methyl-1H-pyrazol-4-yl)quinoline- 2-carboxamide Calc'd 403.2, Found 403.2 7-34

7-[(2,6- dimethylpyridin-4- yl)methyl]-8-fluoro-4- (1-methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 390.2, Found 390.2 7-35

8-fluoro-7-[(2- methoxy-6- methylpyridin-4- yl)methyl]-4-(1-methyl-1H-pyrazol-4- yl)quinoline-2- carboxamide Calc'd 406.2, Found406.2 7-36

8-fluoro-4-(1-methyl- 1H-pyrazol-4-yl)-7-{[3- (trifluoromethyl)piperidin-1-yl] methyl}quinoline-2- carboxamide Calc'd 436.2, Found436.2 7-37

7-[(6- cyclopropylpyridin-3- yl)methyl]-8-fluoro-4-(1-methyl-1H-pyrazol- 4-yl)quinoline-2- carboxamide Calc'd 402.2, Found402.2 7-38

8-fluoro-7-[(6- methoxypyridin-3- yl)methyl]-4-(1- methyl-1H-pyrazol-4-yl)quinoline-2- carboxamide Calc'd 392.2, Found 392.1

Example 8.1 Synthesis of 7-[2-(6-chloropyridin-3-yl)-1(R orS)-hydroxyethyl]-4-(4-fluorophenyl)quinoline-2-carboxamide (8-1 (IsomerA), 8-2 (Isomer B)) 7-[2-(6-Chloropyridin-3-yl)-1(R orS)-hydroxyethyl]-4-(4-fluorophenyl)quinoline-2-carboxamide (8-1, 8-2)

To a stirred solution of4-(4-fluorophenyl)-7-formylquinoline-2-carboxamide (275 mg, 0.934 mmol)and THF (2336 μl) was added (2-chloro-5-pyridyl)methylzinc chloride(0.5M THF, 9345 μl, 4.67 mmol) dropwise over 1 minute. The solution washeated to 50° C. for 20 minutes. Allowed to cool to ambient temperatureand then was quenched with saturated NH₄Cl. The mixture was xtractedwith EtOAc. The organic portion was washed with brine, dried (MgSO₄) andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with CHCl₃ to 70:25:5 CHCl₃/EtOAc/MeOH to give theracemic amide as a colorless solid. The racemic amide was purified bypreparative HPLC Chiralpak AD, eluting with 60% EtOH/hexanes+0.1% Et₂NH,50 ml/min to give 8-1 (isomer A, 38 mg, 0.090 mmol, 9.64% yield) as acolorless solid and 8-2 (isomer B, 43 mg, 0.102 mmol, 10.91% yield) as acolorless solid.

8-1 (LCMS, LRMS m/z (M+H)⁺ 422.2 found, 422.8 required.

8-2 LCMS, LRMS m/z (M+H)⁺ 422.2 found, 422.8 required.

Example 8.2 Synthesis of7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxamide(8-7) 7-Chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile(8-3)

To a stirred solution of 4,7-dichloroquinoline-2-carbonitrile (6 g, 26.9mmol), (2-fluoro-4-methoxyphenyl)boronic acid (5.03 g, 29.6 mmol), 2Msodium carbonate (29.6 ml, 59.2 mmol) in 10:1 toluene (48.9 ml) ethanol(4.89 ml) was added tetrakis(triphenylphosphine)palladium(O) (0.777 g,0.672 mmol). The mixture was stirred at 75° C. under N₂ for 18 hours.The reaction was allowed to cool to ambient temperature. The cooledreaction mixture was diluted with EtOAc and then washed with H₂O, brine,dried (MgSO₄) and concentrated. The residue was mostly dissolved in warmEtOAc (100 ml), added 100 ml of Et₂O, allowed to stand at ambienttemperature for 1 hour. The solid was collected and washed with coldEt₂O (50 ml) to give7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g,14.07 mmol, 52.3% yield) as a yellow solid.

(LCMS, LRMS m/z (M+H)⁺ 313.1 found, 313.7 required.

Methyl 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate(8-4)

7-Chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g,14.07 mmol) was suspended in MeOH (70.3 ml), added 200 ml sat HCl/MeOHand then heated to 60° C. for 4 hours. The reaction was allowed to coolto ambient temperature and then was concentrated. The residue wasdissolved in EtOAc and then washed with 1:1 1N NaOH/sat NaHCO₃, brine,dried (MgSO₄) and concentrated to afford methyl7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (4.4 g,12.73 mmol, 90% yield) as a yellow solid.

(LCMS, LRMS m/z (M+H)⁺ 346.2 found, 346.8 required.

Methyl 7-ethenyl-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate(8-5)

Methyl 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (1.8g, 5.21 mmol) was dissolved in dioxane (23.43 ml), degassed 10 minuteswith N₂. Added potassium vinyltrifluoroborate (1.395 g, 10.41 mmol),palladium(II) acetate (0.088 g, 0.390 mmol),2-bicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.321 g, 0.781 mmol)and cesium carbonate (5.09 g, 15.62 mmol) followed by degassed water(2.60 ml). Degassed with N2 for another 10 minutes and then the mixturewas stirred at 85° C. for 1 hour. Reaction was complete. The reactionmixture was cooled to ambient temperature and then diluted with EtOAc.Partitioned EtOAc with water, washed EtOAc extract with brine, driedusing anhy. MgSO₄ and then concentrated. The residue was purified bycolumn chromatography on silica gel, eluting with hexanes to EtOAc toafford methyl7-ethenyl-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (1.25 g,3.71 mmol, 71.2% yield) as a yellow solid.

(LCMS, LRMS m/z (M+H)⁺ 338.3 found, 338.3 required.

Methyl7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate(8-6)

Methyl 7-ethenyl-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate(250 mg, 0.741 mmol) was dissolved in THF (1.3 ml), heated to 60° C. andthen added 9-BBN (0.5M THF, 1.85 ml, 0.93 mmol) dropwise over 5 minutes.After 1 hour, allowed to cool to ambient. Added5-bromopyridine-2-carbonitrile (203 mg, 1.112 mmol), Pd₂(dba)₃ (33.9 mg,0.037 mmol), butyldi-1-adamantylphosphine (26.6 mg, 0.074 mmol),potassium carbonate (410 mg, 2.96 mmol) and water (135 degassed 5minutes with N₂ and then heated to 90° C. in a sealed tube for 30minutes. Reaction proceeded, allowed to cool to ambient. Added brine andthen EtOAc. The organic portion was collected, dried (MgSO₄) andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with hexanes to EtOAc to afford methyl7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate(160 mg, 0.362 mmol, 48.9% yield) as an orange oil.

(LCMS, LRMS m/z (M+H)⁺ 442.3 found, 442.4 required.

7-[2-(6-Cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxamide(8-7)

A stirred solution of methyl7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate(160 mg, 0.362 mmol) and MeOH (1450 μl) was treated with 5 ml 7NNH₃/MeOH and then heated to 60° C. in a sealed tube for 30 minutes. Thereaction was allowed to cool to ambient temperature and then wasconcentrated. The solid was triturated with EtOH, collected, washed with5 ml Et₂O and then dried in vacuo to afford7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxamide(105 mg, 0.246 mmol, 67.9% yield) as a colorless solid.

(LCMS, LRMS m/z (M+H)⁺ 427.3 found, 427.4 required.

¹H NMR (500 MHz, DMSO): 8.68 (1H, s), 8.27 (1H, s), 8.01 (1H, s), 7.97(3H, s), 7.83 (1H, s), 7.64 (2H, d, J=4.55 Hz), 7.49 (1H, t, J=8.59 Hz),7.09 (1H, d, J=12.11 Hz), 7.02 (1H, d, J=8.60 Hz), 3.89 (3H, s), 3.19(4H, dd, J=18.34, 7.14 Hz).

Example 8.3 Synthesis of4-(2-fluoro-4-methoxyphenyl)-7-[1-(2-methylpyrimidin-5-yl)propan-2(R orS)-yl]quinoline-2-carboxamide (8-10, 8-11) Methyl4-(2-fluoro-4-methoxyphenyl)-7-(prop-1-en-2-yl)quinoline-2-carboxylate(8-8)

Isopropenylboronic acid pinacol ester (2.67 g, 15.91 mmol), methyl7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (5 g, 14.46mmol), potassium phosphate tribasic (9.21 g, 43.4 mmol) and dioxane(43.8 ml)/water (4.38 ml) were combined and then degassed with nitrogenfor 5 minutes. Added palladium(II) acetate (0.243 g, 1.085 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene (0.515 g, 1.085 mmol) and thenheated to 85° C. for 4 hours. Reaction was complete and was allowed tocool to ambient temperature. The mixture was diluted with EtOAc and thenwashed with H₂O, brine, dried (MgSO₄) and concentrated. The residue waspurified by column chromatography on silica gel, eluting with hexanes toEtOAc to afford methyl4-(2-fluoro-4-methoxyphenyl)-7-(prop-1-en-2-yl)quinoline-2-carboxylate(3.3 g, 9.39 mmol, 64.9% yield) as a yellow solid.

(LCMS, LRMS m/z (M+H)⁺ 352.3 found, 352.4 required.

Methyl4-(2-fluoro-4-methoxyphenyl)-7-[1-(2-methylpyrimidin-5-yl)propan-2-yl]quinoline-2-carboxylate(8-9)

Methyl4-(2-fluoro-4-methoxyphenyl)-7-(prop-1-en-2-yl)quinoline-2-carboxylate(1.5 g, 4.27 mmol) was dissolved in THF (7.8 ml), heated to 60° C. andthen added 9-BBN (0.5M THF, 10.7 ml, 5.35 mmol) dropwise over 5 minutes.After 1 hour, allowed to cool to ambient. Added5-bromo-2-methylpyrimidine (0.886 g, 5.12 mmol), Pd₂(dba)₃ (0.195 g,0.213 mmol), butyldi-1-adamantylphosphine (0.153 g, 0.427 mmol),potassium carbonate (2.360 g, 17.08 mmol) and water (0.776 ml), degassed5 minutes with nitrogen and then heated to 90° C. in a sealed tube for30 minutes. The reaction was allowed to cool to ambient temperature. Tothe mixture was added brine and then EtOAc. The organic portion wascollected, dried (MgSO₄) and then concentrated. The residue was purifiedby column chromatography on silica gel, eluting with CHCl₃ to 70:25:5CHCl₃/EtOAc/MeOH to afford methyl4-(2-fluoro-4-methoxyphenyl)-7-[1-(2-methylpyrimidin-5-yl)propan-2-yl]quinoline-2-carboxylate(335 mg, 0.752 mmol, 17.62% yield) as an orange oil.

(LCMS, LRMS m/z (M+H)⁺ 446.4 found, 446.5 required.

4-(2-Fluoro-4-methoxyphenyl)-7-[1-(2-methylpyrimidin-5-yl)propan-2(R orS)-yl]quinoline-2-carboxamide (8-10, 8-11)

A stirred solution of methyl4-(2-fluoro-4-methoxyphenyl)-7-[1-(2-methylpyrimidin-5-yl)propan-2-yl]quinoline-2-carboxylate(335 mg, 0.752 mmol) and MeOH (3008 μl) was treated with 5 ml 7NNH₃/MeOH and then heated to 60° C. in a sealed tube for 30 minutes. Thereaction was allowed to cool to ambient temperature and then wasconcentrated. The solid was azeotroped with 5 ml Et₂O and then dried invacuo to give racemic product as a colorless foam.

The residue was purified by preparative HPLC Chiralpak AD, 5 cm, 40ml/min, eluting with 100% EtOH, to afford 8-10 (isomer A, 95 mg, 0.221mmol, 58.7% yield) as a colorless foam and 8-11 (isomer B, 85 mg, 0.197mmol, 52.5% yield) as a colorless foam.

8-10, Isomer A (LCMS, LRMS m/z (M+H)⁺ 431.3 found, 431.5 required.

¹H NMR (500 MHz, CDCl₃):8.32 (2H, s), 8.21 (1H, s), 8.05 (1H, s), 7.89(1H, s), 7.73 (1H, d, J=8.58 Hz), 7.41 (1H, d, J=8.42 Hz), 7.34 (1H, t,J=8.40 Hz), 6.89-6.85 (1H, m), 6.80 (1H, dd, J=11.53, 2.48 Hz), 5.61(1H, s), 3.90 (3H, s), 3.26-3.21 (1H, m), 3.00-2.92 (2H, m), 2.65 (3H,s). 8-11, Isomer B (LCMS, LRMS m/z (M+H)⁺ 431.4 found, 431.5 required.

¹H NMR (500 MHz, CDCl₃):8.32 (2H, s), 8.21 (1H, s), 8.05 (1H, s), 7.89(1H, s), 7.73 (1H, dd, J=8.63, 2.83 Hz), 7.41 (1H, d, J=8.49 Hz), 7.34(1H, t, J=8.43 Hz), 6.87 (1H, dd, J=8.51, 2.54 Hz), 6.80 (1H, dd,J=11.56, 2.53 Hz), 5.61 (1H, s), 3.90 (3H, s), 3.26-3.21 (1H, m),3.01-2.90 (2H, m), 2.65 (3H, s).

The following compounds have been prepared according to proceduressimilar to those found in Scheme 8.1, 8.2, and 8.3 selecting theappropriate quinoline derivative, boronic acid derivatives, and aryl orheteroaryl halide and provide examples of compounds in the invention.

TABLE 8 Exact IUPAC Mass Example Structure Name [M + H]⁺ 8-12

4-(4-fluorophenyl)-7- (2-pyridin-2- ylethyl)quinoline-2- carboxamideCalc'd 372.2, Found 372.2 8-13

4-(4-fluorophenyl)-7- (2-pyrimidin-5-ylethyl) quinoline-2- carbonitrileCalc'd 355.1, Found 355.1 8-14

4-(4-fluorophenyl)-7- (2-pyridin-4- ylethyl)quinoline-2- carboxamideCalc'd 372.2, Found 372.2 8-15

4-(4-fluorophenyl)-7- (2-pyrimidin-5- ylethyl)quinoline-2- carboxamideCalc'd 373.1, Found 373.1 8-16

4-(4-fluorophenyl)-7- (2-pyridin-3- ylethyl)quinoline-2- carboxamideCalc'd 372.2, Found 372.2 8-17

4-(4-fluorophenyl)-7- (1-hydroxy-2- pyridin-3- ylethyl)quinoline-2-carboxamide Calc'd 388.1, Found 388.1 8-18

4-(4-fluorophenyl)-7- (1-hydroxy-2- pyridin-3- ylethyl)quinoline-2-carboxamide Calc'd 388.1, Found 388.1 8-19

4-(4- methoxyphenyl)-7- [2-(2- methylpyrimidin-5- yl)ethyl]quinoline-2-carboxamide Calc'd 399.2, Found 399.1 8-20

7-[2-(6- chloropyridin-3-yl)- 1-hydroxyethyl]-4-(4- methoxyphenyl)quinoline-2- carboxamide Calc'd 434.1, Found 434.0 8-21

4-(4-fluorophenyl)-7- [1-hydroxy-2-(6- methylpyridin-3-yl)ethyl]quinoline-2- carboxamide Calc'd 402.2, Found 402.2 8-22

4-(4-fluorophenyl)-7- [1-hydroxy-2-(6- methylpyridin-3-yl)ethyl]quinoline-2- carboxamide Calc'd 402.2, Found 402.2 8-23

4-(4-fluorophenyl)-7- (1-methyl-2-pyridin- 3-ylethyl)quinoline-2-carboxamide Calc'd 386.2, Found 386.2 8-24

4-(4-fluorophenyl)-7- (1-methyl-2-pyridin- 3-ylethyl)quinoline-2-carboxamide Calc'd 386.2, Found 386.2 8-25

4-(4-fluorophenyl)-7- [1-methyl-2-(6- methylpyridin-3-yl)ethyl]quinoline-2- carboxamide Calc'd 400.2, Found 400.2 8-26

4-(4-fluorophenyl)-7- [1-methyl-2-(6- methylpyridin-3-yl)ethyl]quinoline-2- carboxamide Calc'd 400.2, Found 400.2 8-27

7-[2-(6- chloropyridin-3-yl)- 1-hydroxyethyl]-4-(4- methoxyphenyl)quinoline-2- carboxamide Calc'd 434.1, Found 434.5 8-28

7-[2-(6- chloropyridin-3-yl)- 1-hydroxyethyl]-4-(4- methoxyphenyl)quinoline-2- carboxamide Calc'd 434.1, Found 434.5 8-29

4-(2-fluoro-4- methoxyphenyl)-7- [2-(2- methylpyrimidin-5-yl)ethyl]quinoline-2- carboxamide Calc'd 417.2, Found 417.2 8-30

7-[2-(2- aminopyridin-3- yl)ethyl]-4-(4- methoxyphenyl) quinoline-2-carboxamide Calc'd 399.2, Found 399.4 8-31

7-[2-(2- aminopyridin-3- yl)ethyl]-4-(2-fluoro- 4-methoxyphenyl)quinoline-2- carboxamide Calc'd 417.2, Found 417.4 8-32

7-[2-(2- cyanopyrimidin-5- yl)ethyl]-4-(4- methoxyphenyl) quinoline-2-carboxamide Calc'd 410.2, Found 410.5 8-33

7-[2-(2- cyanopyrimidin-5- yl)ethyl]-4-(2-fluoro- 4-methoxyphenyl)quinoline-2- carboxamide Calc'd 428.2, Found 428.4 8-34

7-[2-(2- cyanopyrimidin-5- yl)-1-methylethyl]-4- (4-methoxyphenyl)quinoline-2- carboxamide Calc'd 424.2, Found 424.5 8-35

7-[2-(4- aminopyrimidin-5- yl)ethyl]-4-(4- methoxyphenyl) quinoline-2-carboxamide Calc'd 400.2, Found 400.5 8-36

7-[2-(2- aminopyridin-3-yl)-1- methylethyl]-4-(4- methoxyphenyl)quinoline-2- carboxamide Calc'd 413.2, Found 413.5 8-37

7-[2-(2- aminopyridin-3-yl)-1- methylethyl]-4-(4- methoxyphenyl)quinoline-2- carboxamide Calc'd 413.2, Found 413.5 8-38

7-[2-(2- aminopyridin-3-yl)- 1-methylethyl]-4- (2-fluoro-4-methoxyphenyl) quinoline-2- carboxamide Calc'd 431.2, Found 431.5 8-39

7-[2-(2- aminopyridin-3-yl)-1- methylethyl]-4- (2-fluoro-4-methoxyphenyl) quinoline-2- carboxamide Calc'd 431.2, Found 431.5 8-40

4-(4- methoxyphenyl)-7- (1-methyl-2-pyridin- 3-ylethyl)quinoline-2-carboxamide Calc'd 398.2, Found 398.4 8-41

4-(4- methoxyphenyl)-7- (1-methyl-2-pyridin- 3-ylethyl)quinoline-2-carboxamide Calc'd 398.2, Found 398.4 8-42

4-(4- methoxyphenyl)-7- [1-methyl-2-(6- methylpyridin-3-yl)ethyl]quinoline-2- carboxamide Calc'd 412.2, Found 412.4 8-43

4-(4- methoxyphenyl)-7- [1-methyl-2-(6- methylpyridin-3-yl)ethyl]quinoline-2- carboxamide Calc'd 412.2, Found 412.4 8-44

4-(2-fluoro-4- methoxyphenyl)-7- (1-methyl-2-pyridin-3-ylethyl)quinoline- 2-carboxamide Calc'd 416.2, Found 416.4 8-45

4-(2-fluoro-4- methoxyphenyl)-7- (1-methyl-2-pyridin-3-ylethyl)quinoline- 2-carboxamide Calc'd 416.2, Found 416.4 8-46

7-{2-[6- (fluoromethyl) pyridin-3-yl]-1- methylethyl}-4-(4-methoxyphenyl) quinoline-2- carboxamide Calc'd 430.2, Found 430.4 8-47

7-{2-[6- (fluoromethyl)pyridin-3- yl]-1-methylethyl}-4-(4-methoxyphenyl) quinoline-2- carboxamide Calc'd 430.2, Found 430.48-48

4-(2-fluoro-4- methoxyphenyl)-7- {2-[6-(fluoromethyl) pyridin-3-yl]-1-methylethyl} quinoline-2- carboxamide Calc'd 448.2, Found 448.4 8-49

4-(2-fluoro-4- methoxyphenyl)-7- {2-[6-(fluoromethyl) pyridin-3-yl]-1-methylethyl} quinoline-2- carboxamide Calc'd 448.2, Found 448.4 8-50

4-(3-fluoro-4- methoxyphenyl)-7- [2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2- carboxamide Calc'd 417.2, Found 417.3 8-51

4-(2,6-difluoro-4- methoxyphenyl)-7- [2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2- carboxamide Calc'd 435.2, Found 435.3 8-52

4-(4-methoxy-3- methylphenyl)-7-[2- (2-methylpyrimidin-5-yl)ethyl]quinoline- 2-carboxamide Calc'd 413.2, Found 413.3 8-53

4-(4-methoxy-2,6- dimethylphenyl)-7- [2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2- carboxamide Calc'd 427.2, Found 427.3 8-54

4-(3,5-difluoro-4- methoxyphenyl)-7- [2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2- carboxamide Calc'd 435.2, Found 435.3 8-55

4-(3,4- dimethoxyphenyl)-7- [2-(2-methylpyrimidin-5-yl)ethyl]quinoline-2- carboxamide Calc'd 429.2, Found 429.4

Biological Assays

The utility of the compounds in accordance with the present invention asantagonists of metabotropic glutamate receptor activity, in particularmGluR2 activity, may be demonstrated by methodology known in the art.Antagonist constants are determined as follows. The compounds of thepresent invention were tested in a fluorescence laser imaging platereader based assay. This assay is a common functional assay to monitorCa2+ mobilization in whole cells expressing recombinant receptor coupledwith a promiscuous G-protein. CHO dhfr-cells stably expressingrecombinant human mGluR2 and Gα16 loaded with Fluo-4 AM (Invitrogen,Carlsbad Calif.) are treated with various concentrations of antagonistsof compounds and the Ca2+ response is monitored on a FLIPR384 (MolecularDevices, Sunnydale Calif.) for agonist activity. Then 2,500 nM glutamateis added and the antagonist response is monitored. The maximum calciumresponse at each concentration of compound for agonist or antagonistwere plotted as dose responses and the curves were fitted with a fourparameter logistic equation giving IC₅₀ and Hill coefficient using theiterative non linear curve fitting software ADA (Merck & Co). Inparticular, the compounds of the examples shown in the tables above hadactivity in antagonizing the mGluR2 receptor in the aforementionedassays, with an IC₅₀ of less than about 700 nM, indicating theiractivity as antagonists of mGluR2 function. Specific IC 50 values forrepresentative example compounds of the invention are provided in thetable below:

Example IC₅₀ Value (nM) 1-7 159 1-9 171 1-10 660 1-11 822 1-12 678 1-13641 1-14 667 1-15 169 1-16 681 1-17 368 1-18 58 1-19 100 1-20 139 1-21124 1-22 505 1-23 135 1-24 169 1-25 407 1-26 217 1-27 377 1-28 393 1-29190 2-3 21 2-7 9 2-8 38 2-9 416 2-10 21 2-11 25 2-12 475 2-13 71 2-14 302-15 64 2-16 59 2-17 398 2-18 28 2-19 588 2-20 27 2-21 23 2-22 47 2-23456 2-24 12 2-25 16 2-26 29 2-27 7 2-28 17 2-29 5 2-30 123 2-31 109 2-32129 2-33 42 2-34 105 2-35 228 2-36 3059 2-37 59 2-38 27 2-39 8 3-2 463-6 21 3-7 24 3-10 63 3-11 31 3-15 85 3-16 21 3-17 74 3-18 36 3-19 1123-20 21 3-21 40 3-22 47 3-23 192 3-24 31 3-25 43 3-26 25 3-27 23 3-28 843-29 64 3-30 31 3-31 54 3-32 23 3-33 69 3-34 55 3-35 27 3-36 189 3-37 423-38 24 3-39 73 3-40 81 3-41 89 3-42 46 3-43 66 3-44 15 3-45 19 3-46 2063-47 67 3-48 16 3-49 16 3-50 15 3-51 10 4-1 163 4-9 11 4-16 13 4-22-A 94-22- B 11 4-23 137 4-24 78 4-25 61 4-26 118 4-27 183 4-28 82 4-29 824-30 241 4-31 84 4-32 478 4-33 138 4-34 330 4-35 187 4-36 274 4-37 554-38 57 4-39 42 4-40 392 4-41 118 4-42 56 4-43 252 4-44 59 4-45 136 4-4624 4-47 170 4-48 53 4-49 38 4-50 381 4-51 9 4-52 93 4-53 25 4-54 12 4-5533 4-56 88 4-57 237 4-58 163 4-59 394 4-60 196 4-61 166 4-62 252 4-63 464-64 73 4-65 17 4-66 16 4-67 1153 4-68 149 4-69 46 4-70 114 4-71 25 4-72243 4-73 30 4-74 91 4-75 1090 4-76 261 4-77 15 4-78 81 4-79 159 4-80 154-81 1629 4-82 188 4-83 513 4-84 11 4-85 15 4-86 9 4-87 14 4-88 14 4-89235 4-90 8 4-91 8 4-92 17 4-93 66 4-94 63 4-95 11 4-96 8 4-97 260 4-9852 4-99 55 4-100 24 4-101 10 4-102 10 4-103 114 4-104 120 4-105 1724-106 50 4-107 25 4-108 161 4-109 116 4-110 90 4-111 80 4-112 23 4-11324 4-114 15 4-115 34 4-116 14 4-117 53 4-118 13 4-119 18 4-120 2384-121 >1000 4-122 931 4-123 49 4-124 48 4-125 76 4-126 13 4-127 97 4-128142 4-129 >1000 4-130 245 4-131 112 4-132 149 4-133 272 4-134 86 4-135 85-4 299 5-5 125 5-6 987 6-2 21 6-3 55 6-4 145 6-5 47 6-6 13 6-7 8 6-8 566-9 10 6-10 31 6-11 14 6-12 31 6-13 76 6-14 18 6-15 34 6-16 76 6-17 486-18 35 6-19 41 6-20 15 6-21 6 6-22 42 6-23 28 6-24 25 6-25 7 6-26 127-5 338 7-13 13 7-20-A 14 7-20-B 21 7-21 21 7-22 74 7-23 10 7-24 17 7-2520 7-26 15 7-27 169 7-28 10 7-29 8 7-30 21 7-31 28 7-32 214 7-33 36 7-3439 7-35 14 7-36 13 7-37 30 7-38 39 8-1 10 8-2 15 8-7 13 8-10 7 8-11 68-12 86 8-13 170 8-14 44 8-15 7 8-16 10 8-17 5 8-18 5 8-19 22 8-20 128-21 19 8-22 14 8-23 21 8-24 20 8-25 21 8-26 19 8-27 11 8-28 6 8-29 68-30 9 8-31 9 8-32 7 8-33 6 8-34 8 8-35 7 8-36 15 8-37 16 8-38 33 8-3914 8-40 10 8-41 5 8-42 12 8-43 10 8-44 8 8-45 10 8-46 10 8-47 8 8-48 108-49 9 8-50 4 8-51 5 8-52 27 8-53 52 8-54 11 8-55 96

The following abbreviations may be used throughout the text:

Me=methyl; Et=ethy; t-Bu: =tert-butyl; Ar: =aryl; Ph=phenyl; Bn=benzyl;DCE=dichloroethylene; HMDS=hexamethyldisilazane; DMF:=dimethylformamide;DMFDMA=N,N-dimethylformamide dimethylacetal; THF=tetrahydrofuran;BOP:=benzotriazolyloxytris (dimethylamino) phosphoniumhexafluorophosphate; Boc=tert-butyloxycarbonyl; TEA=triethylamine;TPAP=tetra-n-propyl ammonium perruthenate; NMO=N-methyl morpholineN-oxide; CIZn=Chlorozinc; dppf=diphenylphosphorousferrocenyl;PMB=p-methoxybenzyl; Ms=mesyl; Ac=acetyl; DMSO=dimethylsulfoxide;DCM=dichloromethane; m-CPBA=meta-chloroperoxybenzoic acid;DMEM=Dulbecco's Modified Eagle Medium (High Glucose); FBS=fetal bovineserum; rt=room temperature; aq=aqueous; HPLC=high performance liquidchromatography; MS=mass spectrometry

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

1-20. (canceled)
 21. A method of treating a disease or disorder mediatedby the mGluR₂ receptor, said method comprising administering aneffective amount of an mGluR2 NAM compound of Formula (V):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer, wherein: ring A is a moiety selected fromthe group consisting of: phenyl, —(C₅-C₆) cycloalkyl, —(C₅-C₆)cycloalkyenl, -pyridinyl, pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl,-thiadiazolyl, and -oxazolyl; R^(Q) is selected from the groupconsisting of —CN and —C(O)NH₂; -L- is a bond or a divalent moietyselected from the group consisting of: —(C(R^(1L))₂)_(p)—,

—C(O)—, —S(O)—, and —S(O)₂—; p is 1, 2, or 3; each R^(1L) isindependently selected from the group consisting of H, —CH₃, —CF₃, —OH,—C(O)—, halogen, -cyclopropyl, —O—CH₃, and —O—CF₃; le is selected fromthe group consisting of: (1) heterocycloalkyl, heterocycloalkenyl,wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclicor multicyclic ring systems comprising from 3 to 10 ring atoms in which1, 2, or 3 of the atoms of each said ring system is a ring heteroatomindependently selected from the group consisting of N, S, S(O), S(O)₂,and O, and wherein each said heterocycloalkyl group and each saidheterocycloalkenyl group is unsubstituted or substituted with 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, —CH(OH)cycloalkyl, phenyl,-alkyl-phenyl, monocyclic heteroaryl, monocyclic heteroaryl, —(C₃-C₈)spirocycloalkyl, —(C₃-C₈) spiroheterocycloalkyl, —C(O)H, —C(O)OH,—C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl, —N(R^(1A))C(O)—(C₁-C₆) alkyl,—N(R^(1A))₂, —C(O)N(R^(1A))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆)alkyl-phenyl, —S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and—S(O)₂—(C₁-C₆) alkyl, wherein each R^(1A) group is independentlyselected from the group consisting of H and —(C₁-C₆ alkyl); (2)heteroaryl, wherein said heteroaryl is a monocyclic or multicyclic ringsystem comprising from 5 to 10 ring atoms in which from 1 to 4 of theatoms of said ring system is a ring nitrogen atom, and wherein saidheteroaryl is unsubstituted or substituted with 1 to 5 groupsindependently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, hydroxy-substituted —(C₁-C₆) alkyl, —(C₁-C₆)alkynyl, —(C₁-C₆) haloalkyl, hydroxy-substituted —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl,-alkyl-monocyclic heteroaryl, —(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH,—C(O)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl, —N(R^(1B))C(O)—(C₁-C₆) alkyl,—N(R^(1B))₂, —C(O)N(R^(1B))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆)alkyl-phenyl, —S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and—S(O)₂—(C₁-C₆) alkyl, wherein each R^(1B) group is independentlyselected from the group consisting of H and —(C₁-C₆ alkyl); (3) phenyl,wherein said phenyl is unsubstituted or substituted with from 1 to 5groups independently selected from the group consisting of oxo, CN, —OH,halogen, —(C₁-C₆) alkyl, —(C₁-C₆) alkynyl, —(C₁-C₆) haloalkyl,—O—(C₁-C₆) alkyl, —(C₃-C₈) cycloalkyl, -alkyl-cycloalkyl,—CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl,—(C₃-C₈) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C₁-C₆) alkyl,—C(O)O(C₁-C₆) alkyl, —N(R^(1C))C(O)—(C₁-C₆) alkyl, —N(R^(1C))₂,—C(O)N(R^(1C))₂, —S(O)₂H, —S(O)-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl,—S(O)₂-phenyl, —S(O)₂—(C₁-C₆) alkyl-phenyl, —S(O)₂OH, and —S(O)₂—(C₁-C₆)alkyl, wherein each R^(1C) group is independently selected from thegroup consisting of H and —(C₁-C₆ alkyl); (4) H, —(C₁-C₆) alkyl; (5)—CH₂N(R^(1D))R^(1E), wherein: R^(1D) is selected from the groupconsisting of H, —(C₁-C₆) alkyl, and —C(O)OR^(1H); and R^(1E) isselected from the group consisting of —O—(C₁-C₆) alkyl,heteroalkyl,-alkyl-C(O)N(R^(1H)), and —C(O)OR^(1H), wherein each R^(1H)is independently selected from the group consisting of H and —(C₁-C₆)alkyl; and (6) —CH₂N(R^(1F))OR^(1G), wherein: R^(IF) is selected fromthe group consisting of H, —(C₁-C₆) alkyl, and —C(O)OR^(1H), whereineach R^(1H) is independently selected from the group consisting of H and—(C₁-C₆) alkyl; and R^(1G) is selected from the group consisting of Hand —(C₁-C₆) alkyl; n is 0, 1, 2, or 3; each R² (when present) isindependently selected from the group consisting of halogen, —CN, —OH,—(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl, —(C₁-C₆) haloalkyl, —O—(C₁-C₆)haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —NH₂,—NH(C₁-C₆)alkyl, —N(C₁-C₆alkyl)₂, —C(O)O(C₁-C₆) alkyl, and phenyl; andR³ is selected from the group consisting of hydrogen and fluorine. 22.The method of claim 21, wherein said disease or disorder is selectedfrom the group consisting of Alzheimer's disease, cognitive impairment,schizophrenia, mood disorder, pain, and sleep disorder.
 23. (canceled)24. (canceled)
 25. The method of claim 21, wherein R¹ is selected fromthe group consisting of heterocycloalkyl and heterocycloalkenyl, whereineach of said heterocycloalkyl and said heterocycloalkenyl contains 1, 2,or 3 ring heteroatoms independently selected from the group consistingof N, S, S(O), S(O)2, and O, and wherein each said heterocycloalkylgroup and each said heterocycloalkenyl group is unsubstituted orsubstituted with 1 to 5 groups independently selected from the groupconsisting of oxo, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl,—N(H)C(O)—(C₁-C₆) alkyl, —C(O)NH₂, —C(O)N(H)(C₁-C₆ alkyl), —C(O)N(C₁-C₆alkyl)₂, phenyl, —(C₃-C₈) spirocycloalkyl, —(C₃-C₈) cycloalkyl, —(C₁-C₆)haloalkyl, and phenyl.
 26. The method of claim 21, wherein R¹ isheteroaryl, wherein said heteroaryl is mono or bicyclic and comprisesfrom 1 to 3 ring nitrogen atoms, and wherein said heteroaryl isunsubstituted or substituted with 1 to 5 groups independently selectedfrom the group consisting of oxo, —CN, —OH, —(C₁-C₆) alkyl, —O—(C₁-C₆)alkyl, —N(H)C(O)—(C₁-C₆) alkyl, —C(O)NH₂, —C(O)N(H)(C₁-C₆ alkyl),—C(O)N(C₁-C₆ alkyl)₂, phenyl, —(C₃-C₈) spirocycloalkyl, —(C₃-C₈)cycloalkyl, —(C₁-C₆) haloalkyl, and phenyl, with the proviso that whenR¹ is not unsubstituted or substituted triazolyl, substitutedoxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl.
 27. Themethod of claim 21, wherein R¹ is phenyl, wherein said phenyl isunsubstituted or substituted with from 1 to 5 groups independentlyselected from the group consisting of halogen, —O—(C₁-C₆) alkyl, CN,—S(O)-phenyl, —S(O)₂-phenyl, —S(O)—(C₁-C₆) alkyl-phenyl, and—S(O)₂—(C₁-C₆) alkyl-phenyl.
 28. The method of claim 21, wherein R¹ isselected from the group consisting of H and —(C₁-C₆) alkyl.
 29. Themethod of claim 21, wherein R¹ is —CH₂N(R^(1D))R^(1E), wherein: R^(1D)is selected from the group consisting of H, —(C₁-C₆) alkyl, and—C(O)OR^(1H); and R^(1E) is selected from the group consisting of—O—(C₁-C₆) alkyl, heteroalkyl, —(C₁-C₆) alkyl-C(O)N(R^(1H)), and—C(O)OR^(1H), wherein each R^(1H) is independently selected from thegroup consisting of H and —(C₁-C₆) alkyl.
 30. The method of claim 21,wherein R¹ is —CH₂N(R^(1F))OR^(1G), wherein: R^(1F) is selected from thegroup consisting of H, —(C₁-C₆) alkyl, and —C(O)OR^(1H), wherein eachR^(1H) is independently selected from the group consisting of H and—(C₁-C₆) alkyl; and R^(1G) is selected from the group consisting of Hand —(C₁-C₆) alkyl; n is 0, 1, 2, or
 3. 31. The method of claim 21,wherein R^(Q) is CN.
 32. The method of claim 21, wherein R^(Q) is—C(O)NH₂.
 33. The method of claim 21, wherein -L- is selected from thegroup consisting of: —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CF₃)—, —CH(CH₃)—,—CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —C(CH₃)₂—, —CH(OH)—, —CH₂CH(OH)—,—CH(OH)CH₂—, —CH(F)—, —C(CH₃)(OH)—, —CH(OCH₃)—,

—C(O)—. —S(O)—, and —S(O)₂—.
 34. The method of claim 21, wherein n is 0,1, 2, or 3; and each R² is independently selected from the groupconsisting of F, Cl, Br, methyl, ethyl, propyl, i-propyl, n-propyl,n-butyl, tert-butyl, —OCH₃, —OCH₂CH₃, —CFH₂, —CF₂H, —CF₃, —CH₂CFH₂,—CH₂CF₂H, —CH₂CF₃, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, and phenyl.35. The method of claim 21, wherein said compound is selected from thegroup consisting of:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer.
 36. The method of claim 21, wherein saidcompound is selected from the group consisting of:

and or a stereoisomer thereof, or a pharmaceutically acceptable salt ofsaid compound or said stereoisomer.
 37. The method of claim 21, whereinsaid compound is selected from the group consisting of:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer.
 38. The method of claim 21, wherein saidcompound is selected from the group consisting of:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer.
 39. The method of claim 21, wherein saidcompound is selected from the group consisting of:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer.
 40. The method of claim 21, wherein saidcompound is selected from the group consisting of:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer.
 41. The method of claim 21, wherein saidcompound is selected from the group consisting of:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer.
 42. The method of claim 21, wherein saidcompound is selected from the group consisting of:


43. The method of claim 21, wherein said compound is selected from thegroup consisting of:

or a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or said stereoisomer.
 44. The method of claim 21, wherein saidcompound is:


45. The method of claim 44, wherein said compound is in the form of apharmaceutically acceptable salt.
 46. The method of claim 21, whereinsaid compound is:


47. The method of claim 46, wherein said compound is in the form of apharmaceutically acceptable salt.
 48. The method of claim 21, whereinsaid compound is:


49. The method of claim 48, wherein said compound is in the form of apharmaceutically acceptable salt.
 50. The method of claim 21, whereinsaid compound is:

or a stereoisomer thereof.
 51. The method of claim 50, wherein saidcompound, or the stereoisomer thereof, is in the form of apharmaceutically acceptable salt.
 52. The method of claim 21, whereinsaid compound is:


53. The method of claim 52, wherein said compound is in the form of apharmaceutically acceptable salt.